Low tryptophan diet for obesity treatment

Abstract

Provided herein is a method of preventing or treating obesity or other metabolic disorders in a subject by administering a controlled diet essentially devoid of tryptophan. Also provided herein are kits and dietary products for use in the method disclosed herein.

Description

Attorney Docket No. UTSDP4183WO2- 1001375086TITLE LOW TRYPTOPHAN DIET FOR OBESITY TREATMENT CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application Serial No.63 / 747,848 filed January 21, 2025, and U.S. Provisional Patent Application Serial No.63 / 809,176 filed May 20, 2025, each of which are incorporated by reference herein in their entirety.ACKNOWLEDGEMENT OF GOVERNMENT SUPPORT

[0002] This invention was made with government support under grant no. CA245548 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND1. Field

[0003] The present disclosure broadly relates to compositions for use as dietary supplements for weight loss and improving metabolic health. The present disclosure relates to low or no tryptophan formulations and methods for using the formulations in the treatment of obesity and / or a metabolic disease.2. Discussion of Related Art

[0004] Obesity is a major public health concern, affecting over 1 billion people worldwide, including 650 million adults and over 150 million children and adolescents. In the United States, more than 42% of adults are classified as obese, a figure that has risen dramatically in recent decades. Obesity is linked to severe health complications, including type 2 diabetes, cardiovascular disease, metabolic disorders, and certain cancers, leading to an increased risk of premature death. Metabolic disorders such as insulin resistance, metabolic syndrome, and dyslipidemia are closely tied to obesity, as excess body fat disrupts normal metabolic function and increases inflammation, contributing to long-term health issues.

[0005] In addition to personal health impacts, obesity places a significant burden on healthcare systems, with annual obesity-related costs in the U.S. exceeding $170 billion. The growing prevalence of metabolic disorders linked to obesity further strains healthcare resources, increasing the need for more effective prevention and treatment strategies. Addressing obesity and its related metabolic complications is essential to improving public health and reducing healthcare costs.

[0006] Though recent developments in the field of obesity treatment have resulted in development of therapeutics, these therapeutics have multiple undesirable side-effects. For - 1 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086instance, Ozempic, which is commonly prescribed for weight-loss, and metabolic diseases is often associated with nausea, vomiting, diarrhea, constipation, abdominal pain, and decreased appetite. Therefore, there is an unmet clinical need for developing new methods to combat this ever-rising global problem.SUMMARY

[0007] In some aspects, disclosed herein is a dietary product comprising at least 3 essential amino acids selected from a group consisting of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, and valine; wherein the dietary product is substantially devoid of tryptophan. In some aspects, the dietary product is for treating or preventing obesity or a metabolic disease in a subject in need thereof.

[0008] In some aspects, the dietary product comprises less than 0.5 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.05 mg, or 0.001 mg of tryptophan per 100 grams of the dietary product. In some aspects, the composition comprises no tryptophan. In some aspects, the dietary product is part of a controlled diet for a subject in need thereof; wherein the controlled diet comprises less than 0.5 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.05 mg, or 0.001 mg of tryptophan per 100 grams of food intake. In some aspects, the product comprises at least 4, at least 5, at least 6, at least 7, or 8 of the essential amino acids (excluding tryptophan). In some aspects, each of the at least 4, at least 5, at least 6, at least 7, or 8 of the essential amino acids are in an amount of 0.01 mg to 10 mg per 100 grams of the dietary product. In some aspects, the dietary product further comprises one or more non-essential amino acids selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, and tyrosine. In some aspects, the dietary product comprises at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or all of the non-essential amino acids. In some aspects, the dietary comprises one or more macronutrient and / or one or more micronutrient source, or any combination thereof. Non-limiting examples of suitable micronutrients comprises one or more vitamins, one or more macro minerals, or one or more trace minerals.

[0009] In some aspects, the dietary product comprises about 7-10 g of leucine, 4-6 g of isoleucine, 4-5 g of valine, 6-8 g of lysine, 1-3 g of methionine, 2-3 g of phenylalanine, 5-7 g of threonine, 1-2 g of histidine, 4-5 g of alanine, 2-3 g of arginine, 9-13 g of aspartic acid, 14-16 g of glutamic acid, 1-2 g of glycine, 4-5 g of proline, 3-5 g of serine, or 2-3 g of tyrosine, or any combination thereof, per 100 g of protein. In some aspects, the dietary product comprises about 7-10 g of leucine, 4-6 g of isoleucine, 4-5 g of valine, 6-8 g of lysine, 1-3 g of methionine, 2-3 g of phenylalanine, 5-7 g of threonine, 1-2 g of histidine, 3-5 g of alanine, 2-3 g of arginine, 9-13 g of aspartic acid, 14-16 g of glutamic acid, 1-2 g of glycine, 4-5 g of proline, 3-5 g of serine, and 2-3 g of tyrosine per 100 g of protein. In some aspects, the dietary product- 2 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086comprises, per kilogram of the dietary product, about 9-13 g of leucine, 6-10 g of isoleucine, 6-10 g of valine, 16-20 g of lysine, 6-10 g of methionine, 6-10 g of phenylalanine, 6-10 g of threonine, 3-6 g of histidine, 2-6 g of alanine, 10-14 g of arginine, 2-6 g of aspartic acid, 38-42 g of glutamic acid, 21-25 g of glycine, 2-6 g of proline, 2-6 g of serine, or 3-7 g of tyrosine, or any combination thereof.

[0010] In some aspects, the dietary product is in the form of a powder, a gel, a solution, a suspension, a paste, a solid, a pellet, a liquid, a liquid concentrate, a powder which may be reconstituted, a shake, a concentrate, a pill, a bar, a tablet, a capsule, injectable solution, or a ready-to-use product.

[0011] In some aspects, the dietary product further comprises a serotonin supplement. Nonlimiting examples of suitable serotonin supplements include 5-hydroxytryptophan (5-HTP), St. John’s Wort, S-adenosylmethionine (SAMe), vitamin B6, L-methylfolate, magnesium, omega-3 fatty acids, or vitamin D.

[0012] In some aspects, the current disclosure also encompasses a method of treating or preventing obesity or a metabolic disease in a subject in need thereof, the method comprising administering a controlled diet to the subject, wherein the controlled diet is substantially devoid of tryptophan. In some aspects, the controlled diet comprises less than 0.5 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.05 mg, or 0.001 mg of tryptophan per 100 grams of food intake. In some aspects, the controlled diet comprises no tryptophan. In some aspects, the controlled diet changes the overall daily calorie intake by the subject by less than 1%-25%. In some aspects, the controlled diet is for less than 6 months, 5 months, 4 months, 3 months, 2 months, 1 month, 3 weeks, or 2 weeks.

[0013] In some aspects, the method comprises administering to the subject a dietary product substantially devoid of tryptophan. In some aspects, the dietary product is a dietary product disclosed herein. In some aspects, dietary product forms at least, or about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% of the subject’s diet. In some aspects, the dietary product comprises at least 4, at least 5, at least 6, at least 7, or all the essential amino acids. In some aspects, the dietary product comprises each of the at least 4, at least 5, at least 6, at least 7, or all of the essential amino acids in an amount of 0.01 mg to 10 mg per 100 grams of the dietary product. In some aspects, the dietary product further comprises one or more non-essential amino acids selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, and tyrosine. In some aspects, the dietary product further comprises at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or all of the non-essential amino acids. In some aspects, the dietary product further comprises one or more macronutrient and / or one or more micronutrient source, or any- 3 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086combination thereof. In some aspects, the dietary product comprises one or more vitamins, one or more macro minerals, or one or more trace minerals. In some aspects, the dietary product comprises one or more lipids, and / or one or more carbohydrates. In some aspects, the method further comprises administering to the subject a serotonin supplement. Nonlimiting examples of serotonin supplements include 5-hydroxytryptophan (5-HTP), St. John’s Wort, S-adenosylmethionine (SAMe), vitamin B6, L-methylfolate, magnesium, omega-3 fatty acids, or vitamin D. In some aspects, the subject is a mammal. In some aspects, the subject is a human. In some aspects, the obesity or the metabolic disease is diabetes (type 1, type 2 [diet-treated, sulfonylurea-treated, long-term insulin-treated], gestational, autoimmune, obese, borderline type), obesity, metabolic syndrome, inflammatory bowel syndrome, diabesity, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia (high LDL, low HDL), postprandial hyperlipemia, insulin resistance, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), hyperglycemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fatty liver disease (from obesity or diabetes), hypertension, or hypertensive nephrosclerosis, or any combination thereof. In some aspects, the method further comprises administering to the subject one or more additional treatments for obesity, and / or for the metabolic disease. In some aspects, the additional treatment for obesity and / or metabolic disease comprises exercise, weight loss medications (e.g., orlistat, GLP-1 receptor agonists like semaglutide, liraglutide), bariatric surgery (e.g., gastric bypass, sleeve gastrectomy), behavioral therapy, insulin sensitizers (e.g., metformin, thiazolidinediones), lipid-lowering agents (e.g., statins, fibrates), antihypertensives (e.g., ACE inhibitors, ARBs), appetite suppressants, or lifestyle interventions, or any combination thereof.

[0014] In some aspects the current disclosure also encompasses a dietary regimen kit comprising meals for a controlled diet, wherein the controlled diet is substantially devoid of tryptophan. In some aspects, the dietary regimen kit comprises a dietary composition as disclosed herein. In some aspects, the meals comprise pre-packaged meals, each comprising less than 0.5 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.05 mg, or 0.001 mg of tryptophan per 100 grams of food. In some aspects, the dietary regimen kit further comprises instructions for using the kit. In some aspects, the dietary regimen kit if for use for treating or preventing obesity, and / or a metabolic disease.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. Aspects of the present disclosure may be better understood by reference to one or more of these drawings in combination with the detailed description of specific aspects presented herein.- 4 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086

[0016] FIGS. 1A-1T show that trypt-out drives fat loss with minimal lean mass wasting and preserved food intake in wild-type and leptin-deficient (ob / ob) mice. FIG. 1A is a schematic outlining an experimental design of synthetic diets lacking single essential amino acids. FIG.1B shows the percentages of fat loss, lean mass loss, and amino acids in proteins. Screening of synthetic diets lacking single essential amino acids identified Trp as a driver for maximum fat loss minimizing muscle mass. Effects of single essential amino acid deprivation diet in fat and lean mass, and percentage of amino acids in proteins are shown. The number was normalized by control diet group. N = 3 per group of diet, male C57BL6 / J mice. FIG. 1 C depicts an experimental design of C57BL6 / J mice in Trp deficient diet. FIG. 1D is a graphical representation of the serum levels of Trp metabolite in C57BL6 / J mice that were in control diet or Trypt-out diet for 3 weeks. FIG. 1E is a graphical representation of final body weight in grams. N = 3 per group of diet, male and female C57BL6 / J mice. FIG. 1F is a graphical representation of cumulative food intake. N = 3 per group of diet, male and female C57BL6 / J mice. FIG. 1G is a graphical representation of results from glucose tolerance test (GTT) intraperitoneal and Area Under the Curve (AUC). N = 3 per group of diet, male C57BL6 / J mice. FIG. 1H shows graphical representations of lean mass and fat mass in grams and in percentage. Data was acquired by Nuclear Magnetic Resonance (MRI). N = 3 per group of diet, male C57BL6 / J mice. FIG. 11 show microscopy images of tissue sections of gonadal white adipose tissue (gWAT), inguinal white adipose tissue (iWAT), brown adipose tissue (BAT), and liver. Transversal sections of 5 pm of thickness were stained with Hematoxylin and Eosin. FIG. 1 J depicts an experimental design of Leptin knockout mice (ob / ob) in Trp deficient diet. FIG. 1K is a graphical representation of serum AST and ALT in the serum of mice 3 weeks WT and DIO mice fed control or Trypt-out diets for 3 weeks. FIG. 1L is a graphical representation of serum levels of Trp metabolite in ob / ob mice in control diet vs Trypt-out diet for 4 weeks. FIG. 1M shows graphical representations of the cumulative food intake and food intake over body weight over 4 weeks. N = 3 per group of diet, male and female ob / ob mice. FIG. 1N is a graphical representation of GTT intraperitoneal and AUC. N = 3 per group of diet, male ob / ob mice. FIG. 10 show images of gWAT, iWAT, BAT and liver of ob / ob. FIG. 1 P show microscopy images of gWAT, iWAT, BAT, and liver tissue sections of ob / ob. Transversal sections of 5 pm of thickness were stained with Hematoxylin and Eosin. FIG. 1Q shows graphical representations of tissue weight in grams of gWAT, iWAT, BAT and liver. N = 4 per group of diet, ob / ob mice. FIG. 1 R shows graphical representations of lean mass and fat mass in grams and percentage. Data was acquired by Nuclear Magnetic Resonance (MRI). N = 3 per group of diet, male ob / ob mice. FIG. 1S is a graphical representation of liver weight in grams. FIG. 1T is a graphical representation of whole body weight of male ob / ob mice that were in control diet or trypt-out diet for 4 weeks and then changed to control diet for 9 more weeks. N= 4 per group male ob / ob mice. Comparisons were done using unpaired t-test.- 5 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086

[0017] FIGS. 2A-2O show that Tryp-out prevents and reverts obesity induced by high fat diet. FIG. 2A is a schematic of an experimental design of FVB mice after diet induced obesity (DIO). FIG. 2B is a graphical representation of body weight in grams of FVB DIO at day 10 and day 20. N = 4 per group, male FVB mice. FIG. 2C is a graphical representation of food intake by body weight during day 10 and day 20. N = 4 per group of diet, male FVB DIO mice. FIG. 2D shows graphical representations of intraperitoneal GTT results and AUG. N = 4 per group of diet, male FVB DIO mice. FIG. 2E shows graphical representations of lean mass and fat mass in grams and in percentage. Data was acquired by Nuclear Magnetic Resonance (MRI). N = 4 per group of diet, male FVB DIO mice. FIG. 2F shows microscopy images of tissue sections from gWAT, iWAT, BAT, and liver of FVB DIO mice. T ransversal sections of 5 pm of thickness were stained with Hematoxylin and Eosin. FIG. 2G depicts an experimental design of C57BL6 / J mice after DIO. FIG. 2H is a graphical representation of body weight in grams of C57BL6 / J mice DIO. N = 3 for control and N=4 Tryp-out group, male C57BL6 / J DIO mice. Unpaired T-test. FIG. 2I shows graphical representations of cumulative food uptake and food intake over body weight. N = 3 for control and N=4 Tryp-out group, male C57BL6 / J DIO mice. Unpaired T-test. FIG. 2J shows graphical representations of lean mass and fat mass in grams and in percentage. Data was acquired by Nuclear Magnetic Resonance (MRI). N = 3 for control and N=4 Tryp-out group, male C57BL6 / J DIO mice. Unpaired T-test. FIG. 2K shows graphical representations of serum levels of AST and ALT in WT and DIO mice that were fed control or Trypt-out diet for 3 weeks. FIG. 2L is a graphical representation of serum triglycerides levels of mice in control and Trypt-out groups. FIG. 2M is a graphical representation of serum cholesterol levels of mice in control and Trypt-out groups. FIG. 2N depicts respiratory exchange rate (RER) measured by indirect calorimetry and represented as area under the curve (AUG). N = 3 per group of diet for male C57BL6 / J mice; N = 3 control diet and N = 4 experimental diets for male C57BL6 / J DIO; N = 3 per group of diet for male ob / ob (10 week) mice; N = 6 per group of diet for male ob / ob (6 week) mice, unpaired T-test. FIG. 20 shows graphical representations of serum leptin and insulin levels in mice in control and Trypt-out groups. Male C57BL6 / J mice. N = 2-5 per group of control diet and n =3 for Trypt-out group. Male C57BL6 / J mice. Comparisons were done using unpaired t-test.

[0018] FIGS. 3A-3Q show that Trypt-out-driven fat loss is not caused by inhibition of translation or depletion of Trp metabolites. FIG. 3A depicts different pathways Trp can be utilized. FIG. 3B depicts an experimental design for puromycylation experiments in vivo. FIG.3C shows puromycylation results imaged using western blots for puromycin of hepatocytes cultures with and without Trp. FIG. 3D depicts 3T3L1 as undifferentiated (control) and differentiated as adipocytes showing western blot adipocyte markers. FIG. 3E shows images of Western blots for puromycin of 3T3L1 cells cultured with increasing amounts of Trp- 6 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086undifferentiated and differentiated. FIG. 3F shows images of Western blots for adipogenesis markers in 3T3L1 cells cultured with increasing amounts of Trp undifferentiated and differentiated. FIG. 3G is a schematic of an in vivo puromycylation approach. FIG. 3H shows images of Western blots for puromycylation in muscle, BAT, gWAT, iWAT and liver of C57BL6 / J mice in the respective diets. FIG. 3I is a graphical representation of amino acids levels in the liver of WT mice that were fed control or Trypt-out for 3 days or 3 weeks. FIG. 3J depicts Trp metabolites (in blue) used in rescue experiments. FIG. 3K is a graphical representation of measurements of Trp derived metabolites in ob / ob male mice serum after being in the different diets. FIG. 3L is a graphical representation of body weight of ob / ob mice that received intraperitoneally (IP) daily different Trp derived metabolites while in Trypt-out diet. FIG. 3M is a graphical representation of body weight of ob / ob male mice after having the microbiome depleted in the respective diets. FIG. 3N is a graphical representation of glutathione metabolomic measurements of BAT, gWAT and iWAT of 10-week ob / ob mice in the respective diets. FIG. 30 is a graphical representation of lipid peroxidation measurements by C11-BODIPY of differentiated 3T3L1 cells cultured in control and Trp deficient media. FIG.3P shows graphical representations of the growth of cells differentiated and undifferentiated in Trp-free media adding Trp, DMS0, ferrostatin inhibitor (F1) and indole-3-pyruvic acid (I3P). FIG. 3Q is a graphical representation of body weights of ob / ob in Trypt-out diet with daily IP injection of vehicle or ferrostatin inhibitor, Li p1. All comparisons were made using unpaired t-test.

[0019] FIGS. 4A-4V show that providing additional energy sources, such as HFD or sucrose, does not rescue the weight loss induced by Trypt-out. FIG. 4A depicts a route of TRp-derived acetyl Coa production in the mitochondria. FIG. 4B is a graphical representation of fold changes of Trp, Kyn, 2-amino adipate, lys, and pipecolate levels in control and Tryp-out WT mice that were fed for 3 days or 3 weeks. FIG. 4C depicts a 10-week-old ob / ob mice experimental design in control and Trypt-out diets. FIG. 4D is an image of ob / ob (10 week) mice in the respective diets. FIG. 4E is a graphical representation of body weights of ob / ob (10 week) mice in the respective diets, shown in grams. FIG. 4F is a graphical representation of food intake per body weight of ob / ob (10 week) mice in the respective diets. FIG. 4G is a graphical representation of blood glucose levels of ob / ob (10 week) mice in the respective diets. FIG.4H depicts an ob / ob mice experimental design in control high fat and high fat Trypt-out diets (HFD lacking Trp). FIG. 4I is an image of ob / ob mice in the respective diets. FIG. 4J is a graphical representation of body weights in grams of the ob / ob mice in the respective diets. FIG. 4K is a graphical representation of food intake per body weight of ob / ob mice in the respective diets. FIG. 4L is a graphical representation of blood glucose levels of ob / ob mice in the respective diets. FIG. 4M depicts WT (Male C57BL6 / J) mice experimental design- 7 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086in control high fat and high fat Trypt-out diets (HFD lacking Trp). FIG. 4N shows graphical representations of body weight and food intake in grams of the WT mice in the respective diets. FIG. 40 shows graphical representations of lean and fat mass in grams and in percentage of WT mice in the respective diets. FIG. 4P show images of tissue sections of gWAT, and iWAT of WT. Transversal sections of 5 pm of thickness were stained with H&E. FIG. 4Q is a graphical representation of blood glucose levels of WT mice in the respective diets. FIG. 4R depicts young (6-week-old) ob / ob mice experimental design for pre-obesity in a control and Trypt-out diet. FIG. 4S shows images of ob / ob (6 week) mice in the respective diets. FIG. 4T is a graphical representation of body weight in grams of the ob / ob (6 week) mice in the respective diets. FIG. 4U is a graphical representation of food intake per body weight of ob / ob (6 week) mice in the respective diets. FIG. 4V is a graphical representation of blood glucose levels of ob / ob (6 week) mice in the respective diets. All comparisons were made using unpaired t-test. All mice were males.

[0020] FIGS. 5A-5U show that Trypt-out reshapes the hepatic transcriptional landscape with modest effects in adipose tissue and minimal effects in muscle. FIG. 5A is a schematic of mice in the different diets and the tissues that were sent for RNA-seq. FIG. 5B depicts KEGG pathways enriched genes in muscle RNA-seq going up or down. FIG. 5C depicts KEGG pathways enriched genes in iWAT RNA-seq going up or down. FIG. 5D depicts KEGG pathways enriched genes in Liver RNA-seq going up or down. FIG. 5E depicts KEGG pathways enriched in proteomics of livers of mice in the different diets. FIG. 5F is a volcano plot of genes enriched in proteomics if the livers of mice in different diets. Cut offs were 70% and p value of 0.1. FIG. 5G depicts genes and proteins upregulated by Tryp-out that are involved in translation including structural components of the ribosome, tRNA ligases and their regulators and translation factors. FIG. 5H is a table of the most downregulated proteins in the liver of Tryp-out mice and their respective function and tryptophan content. FIG. 5I is a schematic showing the pathway of the most downregulated genes in RNA-seq and proteomics. FIG. 5J shows images of Western blots for proteins involved in fat mentalism of livers of WT (C57BL6 / J) mice that were in different diets for 3 weeks. FIG. 5K shows images of Western blots for proteins involved in fat mentalism of livers of ob / ob mice that were in different diets for 4 weeks. FIG. 5L shows images of Western blots for proteins involved in glycolysis and b-oxidation of livers of ob / ob mice that were in different diets for 4 weeks. FIG.5M shows images of Western blots for proteins involved in fat mentalism of livers of ob / ob mice that were in different diets for 4 weeks. FIG. 5N shows images of Western blots for proteins involved in fat mentalism of livers of WT (C57BL6 / J) mice that were in different diets for 3 days. FIG. 50 shows images of Western blots of proteins involved in fat mentalism in livers of WT (C57BL6 / J) mice that were in different diets for 3 weeks can be rescued by IP- 8 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086injections of Trp. FIG. 5P depicts metabolites in iWAT that were measured by metabolomics.FIG. 5Q depicts metabolites in gWAT that were measured by metabolomics. FIG. 5R depicts the TCA cycle. FIG. 5S shows graphical representations of LC-MS / MS measurements of citrate, malate, and fumerate for mice in control or Trypt-out fed diets. FIG. 5T is a graphical representation of caloric output of droppings from control and Tryp-out mice groups. FIG. 5U depicts metabolites of droppings from control and Tryp-out mice groups. All comparisons were made using unpaired t-test.

[0021] FIGS. 6A-6L show that Trp depletion selectively impairs translation of Trp-rich lipogenic enzymes and triggers UPR-ERAD-mediated degradation of FASN. FIG. 6A shows images of Western blots for FASN, Acly, DHCR7, and Tubulin in primary mouse hepatocytes that were cultured overnight in Trp-free DMEM and then transferred to media with or without Trp in the presence or absence of the proteasome inhibitor MG132 for 8 h. FASN protein levels were reduced under Trp-free conditions and rescued by MG132, which indicated proteasome-dependent degradation. Analysis of lipogenic enzymes under Trp-free conditions demonstrated selective sensitivity of FASN, with other enzymes remaining largely unaffected.FIG. 6B depicts culturing hepatocytes in Typ-free media including 13C-Trp for 6 days then analyzing by using LC-MS / MS for free 13C-Trp and proteomics for protein 13C-Trp. FIG. 6C is a graphical representation of percentage of 12C Trp and 13C Trp in normal hepatocytes that were passaged for 7 days in media containing 13C-Trp as the sole Trp source, as analyzed by LC-MS / MS. While nearly all free intracellular Trp was 13C-labeled, only -10% of Trp-containing peptides in cellular proteins incorporated 13C-Trp, which indicated extensive recycling of pre-existing Trp. FIG. 6D is a pie chart depicting 13C-Trp incorporated proteins and their functions. FIG. 6E is a table showing select proteins that incorporated 13C-Trp, where FASN ranked at the top together with ACLY and ACACA. FIG. 6F is a heatmap depicting unfolded protein response (UPR) of control and Trp-out groups. Trp-out induced activation of the unfolded protein response, as shown by increased expression of ATF6- and ATF4-target genes, including CHOP and BIP. FIG. 6G shows Western blot images of PERK, IRE1a, DDIT3 (CHOP), HSPA5 (BIP), and Actin in cells of WT mice fed control or Trypt-out diet for 3 weeks. FIG. 6H shows Western blot images of PERK, IRE1a, DDIT3 (CHOP), HSPA5 (BIP), ATF6, ATF4, SLC7A11, and Actin, in cells of WT mice fed control or Trypt-out diet for 3 days. FIG. 6I shows Western blot images of IRE1a, ERO1-La, DDIT3 (CHOP), HSPA5 (BIP), DPI, ATF4, ATF6, SLC7A11, and Actin, in cells of ob / ob mice fed control or Trypt-out diet for 4 weeks. FIG. 6J shows Western blot images of ATF6, ATF4, DDIT3 (CHOP), ASNS, FGF21, elF2a, SLCA11, and S6K in cells incubated with or in the absence of each of MG132 and Trp for 8 hours and 16 hours. An image of a ponceau stain of the samples is also shown. FIG. 6K shows Western blot images of HERC4, HRD1, ITCH, Ube2K, and- 9 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086Ube2O in cells from WT mice fed control or Trypt-out diet for 3 days. The UPR-regulated ERAD E3 ligase HRD1 may be induced under Tryp-out conditions and promote degradation of FASN, linking Trp depletion to ER stress-dependent proteostasis remodeling. FIG. 6L is a table summarizing the primary functions and relationships to ERAD or UPR of HRD1 (SYVN1), UBE2K, UBE2O, ITCH, and HERC4 genes.

[0022] FIGS. 7A-7G show that FASN inhibition phenocopies Trp-depletion. FIG. 7A shows Western blot images of ATF4, CHOP, and FGF21 in cells incubated with or without FASN inhibitor or Trp for 8 hours and 16 hours. A Ponceau stain of the samples is also shown. FIG.7B shows images of Western blots and Ponceau stain of liver and serum samples from WT control and Trypt-out groups, analyzed for FGF21 and H3. FIG. 7C shows images of Western blots and Ponceau stain of liver and serum samples from ob / ob control and Trypt-out groups, analyzed for FGF21 and H3. FIG. 7D is a graphical representation of body weights of mice in FGF21 KO control and Trypt-out groups over 4 weeks. FIG. 7E is a graphical representation of food intake of mice in FGF21 KO control and Trypt-out groups over 4 weeks. FIG. 7F is a graphical representation of body weights of mice in FGF21 KO HFD control and Trypt-out groups over 4 weeks. FIG. 7G is a graphical representation of food intake of mice in FGF21 KO HFD control and Trypt-out groups over 4 weeks.

[0023] FIG. 8 depicts how a Trypt-out diet may induce ATF6 and ATF4 target genes.

[0024] FIG. 9 depicts how high dietary tryptophan and Trypt-out diet each may affect adipocyte survival and liver lipogenesis.DETAILED DESCRIPTION

[0025] The following detailed description references the accompanying drawings that illustrate various aspects of the present disclosure. The drawings and description are intended to describe aspects of the present disclosure in sufficient detail to enable those skilled in the art to practice the present disclosure. Other components can be utilized, and changes can be made without departing from the scope of the present disclosure. The following description is, therefore, not to be taken in a limiting sense.

[0026] Dietary interventions are common in obesity treatment, yet the effects of depleting individual nutrients on metabolic reprogramming remain underexplored. In some aspects, the current disclosure is based on the surprising discovery that diet lacking tryptophan, referred herein as "Trypt-out," is the only diet that resulted in significant fat mass reduction while preserving lean mass without affecting food consumption. Tryptophan (Trp), one of the nine essential amino acids, is distinguished by its large size and unique chemical structure, featuring the highest carbon count among essential amino acids and an indole ring. This ring grants Trp hydrophobic properties that are critical in protein structure and protein interactions.- 10 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086Trp is the least abundant amino acid in the proteome representing only an average of 1.3% of the protein content. Therefore, the majority of Trp molecules serve as precursors for a wide range of downstream catabolites that can carry specific biological activities including immunoregulation and neuronal signaling.

[0027] Using synthetic diets that each lack one of the nine essential amino acids, their impact on food consumption in fat and lean mass in mice was studied as disclosed in the Examples below. Remarkably, the T rypt-out diet prevented and reversed obesity, fatty liver and improved glucose clearance within a few weeks in hyperphagic leptin knockout mice and in obese mice induced by high fat diet. Furthermore, the Trypt-out diet promoted weight loss even when combined with high dietary fat and sucrose. Respiratory exchange ratio (RER) measurements indicated a shift towards fat oxidation as an energy source. Metabolomic analyses revealed that T rp depletion led to decreased glutathione levels in both white and brown adipose tissues, triggering ferroptosis and subsequent fat reduction. This fat loss was attributed to the death of fat cells, making the effects of dietary Trp depletion long-lasting. Proposed herein is a method of treating obesity and / or related metabolic diseases and disorders by short-term administration of the Trypt-out diet. This represents a safe and effective intervention for achieving sustained weight loss and fatty liver clearance, even in the context of high-fat intake.I. Terminology

[0028] The phraseology and terminology employed herein are for the purpose of description and should not be regarded as limiting. For example, the use of a singular term, such as, “a” is not intended as limiting of the number of items. Also, the use of relational terms such as, but not limited to, “top,” “bottom,” “left,” “right,” “upper,” “lower,” “down,” “up,” and “side,” are used in the description for clarity in specific reference to the figures and are not intended to limit the scope of the present disclosure or the appended claims.

[0029] Any term of degree such as, but not limited to, “substantially” as used in the description and the appended claims, should be understood to include an exact, or a similar, but not exact configuration. For example, “a substantially planar surface” means having an exact planar surface or a similar, but not exact planar surface. Similarly, the terms “about” or “approximately,” as used in the description and the appended claims, should be understood to include the recited values or a value that is three times greater or one third of the recited values. For example, about 3 mm includes all values from 1 mm to 9 mm, and approximately 50 degrees includes all values from 16.6 degrees to 150 degrees. For example, they can refer to less than or equal to ± 5%, such as less than or equal to ± 2%, such as less than or equal to ± 1%, such as less than or equal to ± 0.5%, such as less than or equal to ± 0.2%, such as less than or equal to ± 0.1%, such as less than or equal to ± 0.05%.- 11 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086

[0030] The terms “comprising,” “including,” and “having” are used interchangeably in this disclosure. The terms “comprising,” “including,” and “having” mean to include, but not necessarily be limited to the things so described.

[0031] The terms “or” and “and / or,” as used herein, are to be interpreted as inclusive or meaning any one or any combination. Therefore, “A, B, or C” or “A, B, and / or C” mean any of the following: “A,” “B,” or “C”; “A, and B”; “A, and C”; “B and C”; “A, B, and C.” An exception to this definition will occur only when a combination of elements, functions, steps, or acts are in some way inherently mutually exclusive.

[0032] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this disclosure belongs. The following references provide one of skill with a general definition of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (3rd ed. 2006); The Cambridge Dictionary of Science and Technology (Walker ed., 1990); The Glossary of Genetics, 5th Ed., R. Rieger et al. (2008), The HarperCollins Dictionary of Biology (1991), all of which are incorporated by reference herein. As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise.

[0033] The phraseology and terminology employed herein are for the purpose of description and should not be regarded as limiting. When introducing elements of the present disclosure or the preferred aspects(s) thereof, the articles “a,” “an,” “the,” and “said” are intended to mean that there are one or more of the elements. The terms “comprising,” “including,” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements. Wherever the terms “comprising” or “including” are used, it should be understood the disclosure also expressly contemplates and encompasses additional aspects “consisting of” the disclosed elements, in which additional elements other than the listed elements are not included.

[0034] The term “about” or “approximately,” as used herein, can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the given value. Where particular values are described in the application and claims, unless otherwise stated the term “about” can mean an acceptable error range for the particular value, such as 10% of the value modified by the term “about.” As used herein, the term “about,” can mean relative to the recited value, e.g., amount, dose, temperature, time, percentage, etc., ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%.- 12 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086

[0035] As used herein, “treatment,” “therapy,” and / or “therapy regimen” refer to the clinical intervention made in response to a disease, disorder or physiological condition manifested by a patient or to which a patient may be susceptible. The aim of treatment includes the alleviation or prevention of symptoms, slowing or stopping the progression or worsening of a disease, disorder, or condition and / or the remission of the disease, disorder or condition.

[0036] As used herein, “prevent” or “prevention” refers to eliminating or delaying the onset of a particular disease, disorder or physiological condition, or to the reduction of the degree of severity of a particular disease, disorder or physiological condition, relative to the time and / or degree of onset or severity in the absence of intervention.

[0037] The term “effective amount” or “therapeutically effective amount” refers to an amount sufficient to effect beneficial or desirable biological and / or clinical results. The term “therapeutically effective amount,” as used herein, means an amount of a compound or combination of compounds that ameliorates, attenuates, or eliminates one or more symptoms of obesity, metabolic diseases and related diseases or disorders or delays the onset of one or more symptoms of these disease herein.

[0038] As used herein, “individual,” “subject,” “host,” and “patient” can be used interchangeably herein and refer to any mammalian subject for whom diagnosis, treatment, prophylaxis or therapy is desired, for example, humans, pets, livestock, horses or other animals. As used herein, the term “subject” and “patient” are used interchangeably herein and refer to both human and nonhuman animals. The term “nonhuman animals” of the disclosure includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dog, cat, horse, cow, chickens, amphibians, reptiles, and the like. In some embodiments, the subject can be a human. In other aspects, the subject can be a human in need of treating an obesity or metabolic disorders.

[0039] A dietary product as used herein is a consumable item designed to supplement the diet by providing essential nutrients, bioactive compounds, or other substances that may not be adequately obtained from regular food intake, or to exclude from the diet a particular component. These products aim to support overall health, enhance specific bodily functions, or address nutritional needs. Dietary products can include vitamins, minerals, proteins, amino acids, fatty acids, fiber, probiotics, and herbal extracts, and they are commonly available in various forms such as a powder, a gel, a solution, a suspension, a paste, a solid, a pellet, a liquid, a liquid concentrate, a powder which may be reconstituted, a shake, a concentrate, a pill, a bar, a tablet, a capsule, injectable solution, or a ready-to-use product. In some aspects, the dietary product is not intended to replace a diet but to complement it, and their use is often guided by individual health needs, lifestyle, or specific wellness goals. In some aspects, the- 13 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086dietary product is intended to partially or fully replace an individual’s diet. A dietary product for therapeutic use is a specialized formulation designed to provide or exclude specific nutrients or bioactive compounds aimed at managing or improving health conditions. These products are typically used under medical supervision and are tailored to address deficiencies, support metabolic processes, or alleviate symptoms associated with diseases, recovery from illness, or specific health challenges. They may include macronutrients (proteins, fats, carbohydrates), micronutrients (vitamins, minerals), amino acids, fiber, probiotics, or plant-based extracts, depending on the intended therapeutic effect. Regulatory standards for these products ensure their safety, efficacy, and alignment with medical guidelines.

[0040] Further, as the present disclosure is susceptible to aspects of many different forms, it is intended that the present disclosure be considered as an example of the principles of the present disclosure and not intended to limit the present disclosure to the specific aspects shown and described. Any one of the features of the present disclosure may be used separately or in combination with any other feature. References to the terms “aspect,” “aspects,” and / or the like in the description mean that the feature and / or features being referred to are included in, at least, one aspect of the description. Separate references to the terms “aspect,” “aspects,” and / or the like in the description do not necessarily refer to the same aspect and are also not mutually exclusive unless so stated and / or except as will be readily apparent to those skilled in the art from the description. For example, a feature, structure, process, step, action, or the like described in one aspect may also be included in other aspects but is not necessarily included. Thus, the present disclosure may include a variety of combinations and / or integrations of the aspects described herein. Additionally, all aspects of the present disclosure, as described herein, are not essential for its practice. Likewise, other systems, methods, features, and advantages of the present disclosure will be, or become, apparent to one with skill in the art upon examination of the figures and the description. It is intended that all such additional systems, methods, features, and advantages be included within this description, be within the scope of the present disclosure, and be encompassed by the claims.II. Dietary products

[0041] In some aspects, disclosed herein are dietary products. In some aspects, the dietary products disclosed herein are for intake as replacement, or partial replacement, diets to reduce the intake of tryptophan in the diet. In some aspects, the dietary product comprises one or more amino acids, or amino acid source like proteins and peptides, carbohydrates, lipids, and / or additional components typically present in food products.- 14 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086A. Amino acids and proteins

[0042] In some aspects, the current disclosure encompasses dietary products comprising at least 3 essential amino acids selected from a group consisting of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, and valine; wherein the dietary product is substantially devoid of tryptophan. In some aspects, the current disclosure encompasses dietary products for nutritional therapy of a disease or disorder in a subject in need thereof, wherein the dietary product comprises at least 3 essential amino acids selected from a group consisting of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, and valine; and wherein the dietary product is substantially devoid of tryptophan. In some aspects, the current disclosure encompasses dietary products for nutritional therapy of obesity or a metabolic disease or disorder, wherein the dietary product comprises at least 3 essential amino acids selected from a group consisting of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, and valine; and wherein the dietary product is substantially devoid of tryptophan. The term “dietary product” as used herein encompasses consumable items, including foods, beverages, and supplements, formulated to provide specific nutritional benefits beyond basic sustenance. These products may be designed to enhance overall health, address nutritional deficiencies and / or dietary excesses, and support targeted physiological functions such as metabolism, cognitive performance, immune response, or recovery from physical activity. In some aspects, the dietary product may provide therapeutic benefits to treat, reduce, or reduce the symptoms of, or the likelihood of occurrence of obesity or a metabolic disease or disorder. In some aspects, the dietary product may provide therapeutic benefits to treat, reduce, or reduce the likelihood of occurrence of a neurological disease or disorder. A dietary supplement may comprise, consist essentially of, consist of, or exclude one or more macronutrients, micronutrients, bioactive compounds, and other functional ingredients intended to optimize health and well-being when consumed as part of a diet.

[0043] As used herein, the term “substantially devoid of tryptophan” as used herein may refer to a product with no tryptophan, or low amounts of tryptophan. In some aspects, the dietary product disclosed herein has no tryptophan. In some aspects, the dietary product may include less than, equal to, or about 0.5 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.09 mg, 0.08 mg, 0.07 mg, 0.06 mg, 0.04 mg, 0.03 mg, 0.02 mg, 0.01 mg, 0.009 mg, 0.008 mg, 0.007 mg, 0.006 mg, 0.004 mg, 0.003 mg, 0.002 mg, or 0.001 mg of tryptophan per 100 grams of the dietary product. In some aspects, the dietary product contributes less than about 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, or less of the daily dietary requirement for tryptophan.- 15 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086

[0044] In some aspects, the dietary product comprises, consists essentially of, consists of, or excludes one or more of the essential amino acids selected form histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, and valine, or any combination thereof; wherein the dietary product is substantially devoid of tryptophan. In some aspects, the dietary product may further comprise or exclude one or more non-essential amino acids selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, and tyrosine, or any combination thereof. In some aspects, the dietary product may comprise, or exclude one or more amino acids selected from histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, valine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, and tyrosine, or any combination thereof. In some aspects, the dietary product may comprise all of the amino acids histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, valine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, and tyrosine.

[0045] In some aspects, each of the essential amino acids which is present in the dietary product is present in an amount of less than, equal to, or more than 0.01 mg to 20 mg per 100 grams of the product.

[0046] In some aspects, each of the essential amino acids which is present in the dietary product is present in an amount of at least, equal to, at most 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90, 1.95, 2.00, 2.05, 2.10, 2.15, 2.20, 2.25, 2.30, 2.35, 2.40, 2.45, 2.50, 2.55, 2.60, 2.65, 2.70, 2.75, 2.80, 2.85, 2.90, 2.95, 3.00, 3.05, 3.10, 3.15, 3.20, 3.25, 3.30, 3.35, 3.40, 3.45, 3.50, 3.55, 3.60, 3.65, 3.70, 3.75, 3.80, 3.85, 3.90, 3.95, 4.00, 4.05, 4.10, 4.15, 4.20, 4.25, 4.30, 4.35, 4.40, 4.45, 4.50, 4.55, 4.60, 4.65, 4.70, 4.75, 4.80, 4.85, 4.90, 4.95, 5.00, 5.05, 5.10, 5.15, 5.20, 5.25, 5.30, 5.35, 5.40, 5.45, 5.50, 5.55, 5.60, 5.65, 5.70, 5.75, 5.80, 5.85, 5.90, 5.95, 6.00, 6.05, 6.10, 6.15, 6.20, 6.25, 6.30, 6.35, 6.40, 6.45, 6.50, 6.55, 6.60, 6.65, 6.70, 6.75, 6.80, 6.85, 6.90, 6.95, 7.00, 7.05, 7.10, 7.15, 7.20, 7.25, 7.30, 7.35, 7.40, 7.45, 7.50, 7.55, 7.60, 7.65, 7.70, 7.75, 7.80, 7.85, 7.90, 7.95, 8.00, 8.05, 8.10, 8.15, 8.20, 8.25, 8.30, 8.35, 8.40, 8.45, 8.50, 8.55, 8.60, 8.65, 8.70, 8.75, 8.80, 8.85, 8.90, 8.95, 9.00, 9.05, 9.10, 9.15, 9.20, 9.25, 9.30, 9.35, 9.40, 9.45, 9.50, 9.55, 9.60, 9.65, 9.70, 9.75, 9.80, 9.85, 9.90, 9.95, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg per 100 grams of the product.

[0047] In some aspects, each of the non-essential amino acids which is present in the dietary product is present in an amount of at least, equal to, at most 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90,- 16 - 301447048Attorney Docket No. UTSDP4183WO2- 10013750861.95, 2.00, 2.05, 2.10, 2.15, 2.20, 2.25, 2.30, 2.35, 2.40, 2.45, 2.50, 2.55, 2.60, 2.65, 2.70, 2.75, 2.80, 2.85, 2.90, 2.95, 3.00, 3.05, 3.10, 3.15, 3.20, 3.25, 3.30, 3.35, 3.40, 3.45, 3.50, 3.55, 3.60, 3.65, 3.70, 3.75, 3.80, 3.85, 3.90, 3.95, 4.00, 4.05, 4.10, 4.15, 4.20, 4.25, 4.30, 4.35, 4.40, 4.45, 4.50, 4.55, 4.60, 4.65, 4.70, 4.75, 4.80, 4.85, 4.90, 4.95, 5.00, 5.05, 5.10, 5.15, 5.20, 5.25, 5.30, 5.35, 5.40, 5.45, 5.50, 5.55, 5.60, 5.65, 5.70, 5.75, 5.80, 5.85, 5.90, 5.95, 6.00, 6.05, 6.10, 6.15, 6.20, 6.25, 6.30, 6.35, 6.40, 6.45, 6.50, 6.55, 6.60, 6.65, 6.70, 6.75, 6.80, 6.85, 6.90, 6.95, 7.00, 7.05, 7.10, 7.15, 7.20, 7.25, 7.30, 7.35, 7.40, 7.45, 7.50, 7.55, 7.60, 7.65, 7.70, 7.75, 7.80, 7.85, 7.90, 7.95, 8.00, 8.05, 8.10, 8.15, 8.20, 8.25, 8.30, 8.35, 8.40, 8.45, 8.50, 8.55, 8.60, 8.65, 8.70, 8.75, 8.80, 8.85, 8.90, 8.95, 9.00, 9.05, 9.10, 9.15, 9.20, 9.25, 9.30, 9.35, 9.40, 9.45, 9.50, 9.55, 9.60, 9.65, 9.70, 9.75, 9.80, 9.85, 9.90, 9.95, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg per 100 grams of the product.

[0048] In some aspects, the dietary product comprises at least 3 essential amino acids selected from a group consisting of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, and valine; wherein the dietary product is substantially devoid of tryptophan. In some aspects, the dietary product comprises at least 3, at least 4, at least 5, at least 6, at least 7, or at least 8 essential amino acids, and is substantially devoid of tryptophan. In some aspects, the dietary product comprises about 7-10 g (or any range derivable therein) of leucine, 4-6 g (or any range derivable therein) of isoleucine, 4-5 g (or any range derivable therein) of valine, 6-8 g (or any range derivable therein) of lysine, 1-3 g (or any range derivable therein) of methionine, 2-3 g of phenylalanine, 5-7 g (or any range derivable therein) of threonine, or 1-2 g (or any range derivable therein) of histidine or any combination thereof, per 100 g of protein. In some aspects, the ratio of branched-chain amino acids (leucine:isoleucine:valine) is approximately 2:1:1, which supports muscle protein synthesis and recovery.

[0049] In some aspects, the dietary product comprises at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or all non-essential amino acids. In some aspects, the dietary product comprises one or more of about 4-5 (or any range derivable therein) g of alanine, 2-3 g (or any range derivable therein) of arginine, 9-11 g (or any range derivable therein) of aspartic acid, 14-16 g (or any range derivable therein) of glutamic acid, 1-2 g (or any range derivable therein) of glycine, 4-5 g (or any range derivable therein) of proline, 3-5 g (or any range derivable therein) of serine, or 2-3 g (or any range derivable therein) of tyrosine, or any combination thereof, per 100 g of protein, while being substantially devoid of tryptophan.

[0050] In some aspects, the dietary product comprises, per kilogram of the dietary product, about 9-13 g (or any range derivable therein) of leucine, 6-10 g (or any range derivable therein) of isoleucine, 6-10 g (or any range derivable therein) of valine, 16-20 g (or any range - 17 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086derivable therein) of lysine, 6-10 g (or any range derivable therein) of methionine, 6-10 g (or any range derivable therein) of phenylalanine, 6-10 g (or any range derivable therein) of threonine, 3-6 g (or any range derivable therein) of histidine, 2-6 g (or any range derivable therein) of alanine, 10-14 g (or any range derivable therein) of arginine, 2-6 g (or any range derivable therein) of aspartic acid, 38-42 g (or any range derivable therein) of glutamic acid, 21-25 g (or any range derivable therein) of glycine, 2-6 g (or any range derivable therein) of proline, 2-6 g (or any range derivable therein) of serine, or 3-7 g (or any range derivable therein) of tyrosine, or any combination thereof.

[0051] In some aspects, the dietary product disclosed herein comprises each of the one or more essential and / or non-essential amino acids in amounts similar to those found in commonly known protein supplements, for example, whey protein, soy protein, collagen protein, or plant-based protein, but substantially devoid of tryptophan.

[0052] In some aspects, the dietary product may further comprise one or more amino acid derivatives. Non-limiting examples include creatine, L-carnitine, N-acetyl cysteine (NAC), S-adenosylmethionine (SAMe), beta-alanine, taurine, glutathione, L-theanine, citrulline malate, ornithine, GABA, 5-HTP, acetyl-L-carnitine (ALCAR), arginine alpha-ketoglutarate (AAKG), or any combination thereof.

[0053] In some aspects, the dietary product may comprise isolated amino acids, synthesized amino acids, amino acid derivatives, or sources of amino acids, for example, small peptides or proteins. In some aspects, the peptides or proteins may be isolated or produced using recombinant protein production. In some aspects, the proteins for use in the dietary product are substantially devoid of tryptophan. In some aspects, the proteins may be engineered to be substantially devoid of tryptophan. Methods of recombinant protein production are well known in the art. In some aspects, the recombinant protein is expressed in a yeast, bacterium, animal, or plant cell. In some aspects, the expression cell may be engineered to have a orthologous translation system, such that the expressed protein is substantially devoid of tryptophan.

[0054] In some aspects, the recombinant proteins described herein may be produced in a microorganisms such as yeast and bacteria. Recombinant protein may be expressed in bacteria such as Escherichia coli, Caulobacter crescentus, Rodhobacter sphaeroides, Pseudoalteromonas haloplanktis, Shewanella sp., Pseudomonas putida, P. aeruginosa, P. fluorescens, Halomonas elongate, Chromohalobacter salexigens, Streptomyces lividans, S. griseus, Nocardia lactamdurans, Mycobacterium smegmatis, Corynebacterium glutamicum, C. ammoniagenes, Brevi bacterium lactofermentum, Bacillus subtilis, B. brevis, B. megaterium, B. licheniformis, B. amyloliquefaciens, Lactococcus lactis, L. plantarum, L. casei, L. reuteri, or- 18 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086L gasseri. In some aspects, the recombinant protein is expressed in a eukaryotic microorganism, such as Saccharomyces spp., Kluyveromyces spp., Pichia spp., Aspergillus spp., Tetrahymena spp., Yarrowla spp., Hansenula spp., Blastobotrys spp., Candida spp., Zygosaccharomyces spp., Debrayomyces spp., Fusarium spp., and Trichoderma spp.

[0055] In some aspects, the recombinant proteins are expressed in yeast.

[0056] The recombinant protein may be expressed in one or more cells using genetic sequences (e.g., DNA or RNA sequences) isolated or derived from cow (Bos taurus), goat (Capra hircus), sheep (Ovis aries), water buffalo (Bubalus bubal is), dromedary camel (Camelus dromedaries), Bactrian camel (Camel us bactrianus), wild yak (Bos mutus), horse (Equus caballus), donkey (Equus asinus), reindeer (Rangifer tarandus), Eurasian elk (Alces aloes), alpaca (Vicugna pacos), zebu (Bos indicus), llama (Lama glama), or human (Homo sapiens).

[0057] In some aspects, a genetic sequence used to encode the recombinant protein has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the genetic sequence encoding a protein in one or more of cow (Bos taurus), goat (Capra hircus), sheep (Ovis aries), water buffalo (Bubalus bubalis), dromedary camel (Camelus dromedaries), Bactrian camel (Camelus bactrianus), wild yak (Bos mutus), horse (Equus caballus), donkey (Equus asinus), reindeer (Rangifer tarandus), Eurasian elk (Alces alces), alpaca (Vicugna pacos), zebu (Bos indicus), llama (Lama glama), or human (Homo sapiens). In some aspects, the recombinant protein expressed in a nonmammalian cell has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with a protein from one or more of cow (Bos taurus), goat (Capra hircus), sheep (Ovis aries), water buffalo (Bubalus bubalis), dromedary camel (Camelus dromedaries), Bactrian camel (Camelus bactrianus), wild yak (Bos mutus), horse (Equus caballus), donkey (Equus asinus), reindeer (Rangifer tarandus), Eurasian elk (Alces alces), alpaca (Vicugna pacos), zebu (Bos indicus), llama (Lama glama), or human (Homo sapiens). The recombinant protein may be extracted using standard methods known in the art. For example, the proteins may be extracted using solvent or aqueous extraction or using phenol extraction. Once extracted, the proteins may be maintained in a buffered environment (e.g., Tris, MOPS, HEPES), in order to avoid sudden changes in the pH. The proteins may also be maintained at a particular temperature, such as 4 °C. One or more additives may be used to aid the extraction process (e.g., salts, protease / peptidase inhibitors, osmolytes, reducing agents, etc.)

[0058] In some aspects the protein content of the dietary product comprises less than, more than, or equal to about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%,- 19 - 301447048Attorney Docket No. UTSDP4183WO2- 100137508665%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% amino acids, peptides, or proteins, or derivatives thereof.B. Lipids

[0059] In some aspects, the dietary products provided herein further comprises lipids. Lipids may be critical for sensory characteristics such as mouthfeel and consistency. In addition, lipids provide nutrition and health benefits. Additionally, lipids can influence the flavors and / or aroma of dietary products.

[0060] In some aspects, the dietary products provided herein comprise one or more lipids selected from the group consisting of fats, oils, monoglycerides, diglycerides, triglycerides, phospholipids, and free fatty acids. In some aspects, the dietary products may comprise, consist essentially of, consist of, exclude lipids from an animal source. In some aspects, the dietary products may comprise, consist essentially of, consist of, exclude lipids from an plant source. In some aspects, the dietary products comprise only saturated lipids. In some aspects, the dietary products comprise only unsaturated lipids. In some aspects, the dietary products comprise saturated lipids and unsaturated lipids.

[0061] Non-limiting examples of oils / fats that may be incorporated into the dietary product include, but are not limited to: oils (e.g., sunflower oil, coconut oil, mustard oil, peanut oil, canola oil, corn oil, cottonseed oil, flax seed oil, olive oil, palm oil, rapeseed oil, safflower oil, sesame oil, soybean oil, almond oil, beech nut oil, Brazil nut oil, cashew oil, hazelnut oil, macadamia nut oil, mongongo nut oil, pecan oil, pine nut oil, pistachio nut oil, walnut oil, avocado oil, grape oil), microbe-derived oils, algae-derived oils, fungus-derived oils, marine animal oils (e.g., Atlantic fish oil, pacific fish oil, mediterranean fish oil, light pressed fish oil, alkaline treated fish oil, heat treated fish oil, light and heavy brown fish oil, bonito oil, pilchard oil, tuna oil, sea bass oil, halibut oil, spearfish oil, barracuda oil, cod oil, menhaden oil, sardine oil, anchovy oil, capelin oil, Atlantic cod oil, Atlantic herring oil, Atlantic mackerel oil, Atlantic menhaden oil, salmonid oil, and shark oil, squid oil, cuttlefish oil, octopus oil, krill oil, seal oil, whale oil), non-essential oils, essential oils, natural oils, non-hydrogenated oils, partially hydrogenated oils, hydrogenated oils (e.g., hydrogenated coconut oil), crude oils, semi-refined (also called alkaline refined) oils, and refined oils. In some aspects, longer chain oils (e.g., sunflower oil, corn oil, olive oil, soy oil, peanut oil, walnut oil, almond oil, sesame oil, cottonseed oil, canola oil, safflower oil, flax seed oil, palm oil, palm kernel oil, palm fruit oil, coconut oil, babassu oil, shea butter, mango butter, cocoa butter, wheat germ oil, rice bran oil, engineered sunflower oil that overexpresses oleic acid by 400% combined with short-chain triglycerides to produce transesterified fatty acid esters, tallow, lard, butterfat, chicken fat, duck fat, lecithin, sphingomyelin, sterols, waxes (for example lanolin), essential fatty acids (for example,- 20 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086arachidonic acid, omega-3 fatty acids), and milk lipids. Various combinations of triglycerides and longer chain oils can be incorporated to create a number of different flavor and nutrient profiles.

[0062] Non-limiting examples of monoglycerides and diglycerides include plant-derived monoglycerides and diglycerides (e.g., monoglycerides and diglycerides derived from sunflower, coconut, peanut, cottonseed, olive, palm, rapeseed, safflower, sesame seed, soybean, almond, beech nut, Brazil nut, cashew, hazelnut, macadamia nut, mongongo nut, pecan, pine nut, pistachio, walnut, and avocado). The monoglycerides and diglycerides can include the acyl chain of any of the free fatty acids listed herein. Additional examples of monoglycerides and diglycerides are known in the art.

[0063] Non-limiting examples of free fatty acids include butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, myristoleic acid, pamitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, a-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, omega-fatty acids (e.g., arachidonic acid, omega-3-fatty acids, omega-6-fatty acids, omega-7-fatty acids, omega-9-fatty acids), fatty acids with even number of carbons of 4-16 carbons in length, monosaturated acids (particularly with 18 carbons), fatty acids with low interfacial tension (e.g., less than 20, less than 15, less than 11, less than 9, less than 7, less than 5, less than 3, less than 2, less than 1, or less than 0.5 dynes / cm, from 0.1 to 20, from 1 to 15, from 2 to 9, from 3 to 9, from 4 to 9, from 5 to 9, from 2 to 7, from 0.1 to 5, from 0.3 to 2, or from 0.5 to 1 dynes / cm, 0.1, 0.5, I.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, II.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, or 20.0), butyric (4:0) acid or caproic (6:0) acid that is esterified at sn-3, mediumchain fatty acids (8:0-14:0) as well as 16:0 that are esterified at positions sn-1 and sn-2, fatty acids in which stearic acid (18:0) is placed at position sn-1 , fatty acids in which oleic acid (18:1) is placed at positions sn-1 and sn-3, fatty acids that have a range of carbon atoms (e.g., from 8 to 40, from 10 to 38, from 12 to 36, from 14 to 34, from 16 to 32, from 18 to 30, or from 20 to 28 carbon atoms), fatty acids that comprise at least one unsaturated bond (i.e. , a carboncarbon double or triple bond; e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, or at least 8 carbon-carbon double bonds and / or triple bonds), fatty acids with conjugated unsaturated bonds (i.e., at least one pair of carbon-carbon double and / or triple bonds are bonded together, without a methylene (CH2) group between them, and derivatives of the above named fatty acids (e.g., esters (e.g., methyl and ethyl esters), salts (e.g., sodium and potassium salts), triglyceride derivatives, diglycerides derivatives, monoglyceride derivatives). The free fatty acids can be saturated on unsaturated. In some aspects, the free fatty acids are- 21 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086not derived from or produced by a mammal. Additional examples of free fatty acids are known in the art.

[0064] Non-limiting examples of phospholipids include lecithin phospholipids (e.g., soy lecithin phospholipids, sunflower lecithin phospholipids, cotton lecithin phospholipids, rapeseed lecithin phospholipids, rice bran lecithin phospholipids, and corn lecithin phospholipids), cardiolipin, ceramide phosphocholines, ceramide phosphoethanolamines, glycerophospholipids, phasphatidicacid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphospingolipids, and phsophatidylserine. In some aspects, the phospholipids are not derived from or produced by a mammal. Additional aspects of phospholipids are known in the art.

[0065] Non-limiting examples of triglycerides include tributyrin, short-chain triglycerides, short-chain triglycerides comprising three oleic acids; short-chain triglycerides comprising hexanoic acid; short-chain triglycerides comprising hexanoic acid and butyric acid; short-chain triglycerides comprising hexanoic acid and decanoic acid; and short-chain triglycerides comprising one butyric, one hexanoic, and one octanoic acid. In some aspects, the flavor profiles of the compositions provided herein are modulated by incorporating synthetic shortchain triglycerides combined with plant-based oils (e.g., sunflower oil) in desired combinations. For example, a mixture of (C18 C18 C6) and (C18 C6 C18) provides a different flavor profile than a mixture of (C18 C4 C4) and (C18 C10 C10).

[0066] In some aspects, the dietary products provided herein comprise between 0% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%; between 0.1% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, or 0.2%; between 0.2% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, or 0.3%; between 0.3% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.4%; between 0.4% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5%; between 0.5% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%; between 1% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, or 2%; between 2% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, or 3%; between 3% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, or 4%; between 4% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, or 5%; between 5% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, or 6%; between 6% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, or 7%; between 7% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, or 8%; between 8% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 9%;- 22 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086between 9% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%; between 10% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, or 15%; between 15% and 50%, 45%, 40%, 35%, 30%, 25%, or 20%; between 20% and 50%, 45%, 40%, 35%, 30%, or 25%; between 25% and 50%, 45%, 40%, 35%, or 30%; between 30% and 50%, 45%, 40%, or 35%; between 35% and 50%, 45%, or 40%; between 40% and 50%, or 45%; or between 45% and 50% by weight of lipid.C. Carbohydrates

[0067] In some aspects, the dietary products provided herein further comprise one or more carbohydrates. Carbohydrates, for example sugars, starches and fibers, provide sweetness to the taste profiles and / or serve as fast-acting energy and nutrition sources.

[0068] In some aspects, the dietary products provided herein comprise one or more saccharides (e.g., monosaccharides, disaccharides, polysaccharides). Non-limiting examples of saccharides include glucose, mannose, maltose, fructose, galactose, lactose, sucrose, and tagatose. In some aspects, the dietary products comprise less than 4.5%, less than 4.25%, less than 4%, less than 3.75%, less than 3.5%, less than 3.25%, less than 3%, less than 2.75%, or less than 2.5% by weight of monosaccharides and / or disaccharides.

[0069] In some aspects, the dietary product may comprise one or more starches and / or fibers. Non-limiting examples of starches include com, potato, rice, wheat, arrowroot, guar gum, locust bean, tapioca, arracacha, buckwheat, banana, barley, cassava, konjac, kudzu, oca, sago, sorghum, sweet potato, taro, yams, fruit, vegetable, tuber, legume, cereal grain, pseudograin starch, or any derivative thereof, or any combinations thereof. Non-limiting examples of suitable fiber sources are pea fiber, oat fiber, bamboo fiber, rice bran, waxy maize, bean fiber, beet fiber, guar gum, pectin, carrageenan, apple fiber, citrus fiber, carrot fiber, barley fiber, psyllium husk, soy fiber, sesame flour, flaxseed fiber, nuts, garcinia fiber, chicory fiber, fenugreek fiber, or any derivative thereof, or any combinations thereof. In some aspects, the one or more starches and / or fibers incorporated into the dietary product are substantially devoid of, and or are processed to be substantially devoid of tryptophan.

[0070] In some aspects, the dietary products comprise between 0.001% and 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.01%; between 0.001% and 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1%; between 0.1% and 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5%; between 0.5% and 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%; between 1% and 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, or 2%; between 2% and 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, or 3%; between 3% and 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, or 4%; between 4% and 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, or 5%; between- 23 - 301447048Attorney Docket No. UTSDP4183WO2- 10013750865% and 25%, 20%, 15%, 10%, 9%, 8%, 7%, or 6%; between 6% and 25%, 20%, 15%, 10%, 9%, 8%, or 7%; between 7% and 25%, 20%, 15%, 10%, 9%, or 8%; between 8% and 25%, 20%, 15%, 10%, or 9%; between 9% and 25%, 20%, 15%, or 10%; between 10% and 25%, 20%, or 15%; between 15% and 25%, or 20%; or between 20% and 25% by weight of carbohydrate.

[0071] In some aspects, the dietary products comprise carbohydrates derived essentially from plants. In some aspects, the dietary product comprises carbohydrates derived from both animals and plants.D. Other components

[0072] The dietary products provided herein may comprise one or more other components, for example one or more vitamins, one or more of minerals, hydrocolloids, fibers, salts, binder, flavor enhancer, aromatic elements, starch, gelling agents, thickeners, emulsifiers, or any combination thereof.

[0073] Non-limiting examples of other components include minerals (e.g., fat soluble minerals, water soluble minerals, calcium, phosphorous, potassium, sodium, citrate, chloride, phosphate, magnesium, potassium, zinc, iron, molybdenum, manganese, copper). Minerals can contribute to the structure and stability of the dietary products provided herein by interacting with fat globules and micelles to maintain an emulsified mixture. Minerals can also affect sensory characteristics such as mouthfeel, consistency, and to a certain extent, flavor of the dietary products. Minerals can also improve the nutritional profile of the dietary products.

[0074] Further non-limiting examples of other components include vitamins. Examples of nonlimiting vitamins include lipid soluble vitamins, water soluble vitamins, thiamin (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pantothenic acid (vitamin B5), vitamin B6 (pyridoxine), vitamin B12 (cobalamin), vitamin C, folate, vitamins A, vitamin D, vitamin E, and vitamin K).

[0075] Further non-limiting examples of other components include coloring agents, color enhancers, and color stabilizers (e.g., titanium oxide).

[0076] Further non-limiting examples of other components include taste agents, taste enhancers, and taste stabilizers (e.g., b-decalactone, ethyl butyrate, 2-furyl methyl ketone, 2,3-pentanedione, y-undecalactone, b-undecalactone, natural favors, artificial flavors, triglycerides, hydrolyzed casein, and / or whey protein).

[0077] Further non-limiting examples of other components include sweetening agents (e.g., stevia, aspartame, cyclamate, saccharin, sucralose, mogrosides, brazzein, curculin, erythritol, glycyrrhizin, inulin, isomalt, lacititol, mabinlin, malititol, mannitol, miraculin, monatin, monelin,- 24 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086osladin, pentadin, sorbitol, thaumatin, xylitol, acesulfame potassium, advantame, alitame, aspartame-acesulfame, sodium cyclamate, dulcin, glucin, neohesperidin dihyrdochalcone, neotame, and / or P-4000). In some aspects, the sweetening agents do not comprise carbohydrates.

[0078] Further non-limiting examples of other components include aroma agents, aroma stabilizers, and aroma enhancers (e.g., propylene glycol, glycerol, ethyl alcohol, salt, sugars).

[0079] Further non-limiting examples of other components include shelf life extending agents (e.g., carbon monoxide, nitrites, sodium metabisulfite, Bombal, vitamin E, rosemary extract, greet tea extract, catechins, antioxidants).

[0080] Further non-limiting examples of other components include supramolecules (i.e., complexes of linked molecules (e.g., linked proteins) other than micelles.

[0081] The dietary product may comprise a hydrocolloid. The hydrocolloid may comprise konjac gum, gum Arabic, carrageenan, agar-agar, pectin, alginate, gellan, konjac glucomannan, xanthan, modified starch, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, guar gum, locust bean gum, tara gum, gum tragacanth, gum ghatt, their derivatives, or any combination thereof. The hydrocolloid may comprise konjac flour, methyl cellulose, gum Arabic, carrageenan, or any combination thereof. The hydrocolloid may be about 1 wt % to about 5 wt % of the dietary product.

[0082] The dietary product may comprise a fiber. The fiber may comprise konjac flour, guar gum, xanthan gum, psyllium, chitin, inulin, pectin, dextrin, a starch, a cellulose, a hemicellulose, a starch, a lignin, a citrus fiber extract, or any combination thereof. The plantbased fiber may comprise inulin, gum Arabic, citrus fiber, maltodextrin, or any combination thereof. The fiber may be at least 5 wt %, or about 0.5 wt % to about 8.0 wt % of the product.

[0083] The dietary product may comprise a binder. The binder may comprise starch, gum, methyl cellulose, lecithin, or any combination thereof. The binder may be about 0.25 wt % to about 1.5 wt % of the product.

[0084] In some aspects, the dietary product comprises a buffering agent. In some aspects, the buffering agent maintains the pH of the dietary product. In some aspects, the dietary product has a pH of about 5 to about 8. In some aspects, the dietary product has a pH of less than 8.0, less than 7.5, less than 7, less than 6.5, less than 6, less than 5.5, less than 5, less than 4.9, less than 4.8, less than 4.7, less than 4.6, or less than 4.5; between 3.8 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4, or 3.9; between 3.9 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4; between 4 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1; between 4.1 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, 4.8, 4.7, 4.6, 4.5,- 25 - 301447048Attorney Docket No. UTSDP4183WO2- 10013750864.4, 4.3, 4.2; between 4.2 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3; between 4.3 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4; between 4.4 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, 4.8, 4.7, 4.6, 4.5; between 4.5 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, 4.8, 4.7, 4.6; between 4.6 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, 4.8, 4.7; between 4.7 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, or 4.8; between 4.8 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, or 4.8; between 4.9 and 7.5, 7, 6.5, 6, 5.5, or 5; between 5 and 7.5, 7, 6.5, 6, or 5.5; between 5.5 and 7.5, 7, 6.5, or 6; between 6 and 7.5, 7, or 6.5; between 6.5 and 7.5, or 7; or between 7 and 7.5.

[0085] In some aspects, the dietary product disclosed herein may comprise one or more probiotics. In some aspects, the added probiotics may provide health additional health benefits. In some aspects, the amount and / or the type of probiotics added to the dietary composition disclosed herein is such that it does not contribute substantially to the tryptophan content of the composition. Non-limiting examples of suitable probiotics include Aerococcus, Aspergillus, Bacillus, Bacteroides, Bifidobacterium, Candida, Clostridium, Debaromyces, Enterococcus, Fusobacterium, Lactobacillus, Lactococcus, Leuconostoc, Melissococcus, Micrococcus, Mucor, Oenococcus, Pediococcus, Penicillium, Peptostrepococcus, Pichia, Propionibacterium, Pseudocatenulatum, Rhizopus, Saccharomyces, Staphylococcus, Streptococcus, Torulopsis, Weissella, or a combination thereof. Some specific examples include but are not limited to Lactobacillus acidophilus, Lactobacillus klebsiella, Lactobacillus leuconostoc, Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus plantarum, Lactobacillus caret, Lactobacillus pentoaceticus, Lactobacillus brevis, Lactobacillus thermophilus, and other members of the genera Lactobacillus, Leuconostoc, Pediococcus, Lactococcus, and Streptococcus, as well as the more peripheral Aerococcus, Carnobacterium, Enterococcus, Oenococcus, Sporolactobacillus, Tetragenococcus, Vagococcus, and Weissella that are classified as safe for consumption by humans and / or other animals by a federal or local regulatory agency (e.g., the Federal Food and Drug Agency (FDA)).

[0086] Further non-limiting examples of other components include anti-caking agents, antifoaming agents, anti-inflammatory agents, anti-microbial agents, anti-oxidants, coenzymes, enzymes, essential nutrients, neuroactive compounds, neutraceuticals, nutritional supplements, buffering agents, salts, emulsifiers, stabilizers, and mixtures of any of the other components disclosed herein.

[0087] In certain aspects, the dietary product further comprises one or more serotonin-supporting supplements formulated to mitigate or prevent declines in serotonergic tone that may occur during tryptophan restriction. In some aspects, the dietary product includes 5- hydroxytryptophan (5-HTP) and / or cofactors that support monoamine synthesis and turnover, non-limiting examples of which include vitamin B6 (e.g., pyridoxal-5'-phosphate),- 26 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086L-methylfolate, S-adenosylmethionine (SAMe), magnesium, omega-3 fatty acids (e.g., EPA and / or DHA), and vitamin D, singly or in combination. The serotonin-supporting component can be provided as a premix blended into powdered or ready-to-drink formats, as a microencapsulated beadlet for stability and controlled release, or as a separately packaged sachet to be co-administered with the amino acid base. In some aspects, the composition delivers a unit dose configured for once- or twice-daily administration and may be titratable according to subject weight, clinical scores, or serum / plasma biomarker readouts, while maintaining the dietary product substantially devoid of tryptophan. In kit aspects, the serotonin-supporting component may be provided as a labeled module with use instructions synchronized to on-diet and maintenance phases.

[0088] In some aspects, the dietary product comprises between 0.001% and 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.01%, or 0.005%; between 0.005% and 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01%; between 0.01% and 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05%; between 0.05% and 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1%; between 0.1% and 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5%; between 0.5% and 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%; between 1% and 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, or 2%; between 2% and 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, or 3%; between 3% and 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, or 4%; between 4% and 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%; between 5% and 12%, 11%, 10%, 9%, 8%, 7%, or 6%; between 6% and 12%, 11%, 10%, 9%, 8%, or 7%; between 7% and 12%, 11%, 10%, 9%, or 8%; between 8% and 12%, 11%, 10%, or 9%; between 9% and 12%, 11%, or 10%; between 10% and 12%, or 11%; or between 11% and 12% by weight of any one of the other components disclosed herein.

[0089] In some aspects, the dietary products comprise between 0.001% and 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.01%, or 0.005%; between 0.005% and 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01%; between 0.01% and 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05%; between 0.05% and 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1%; between 0.1% and 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5%; between 0.5% and 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%; between 1% and 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, or 2%; between 2% and 10%, 9%, 8%, 7%, 6%, 5%, 4%, or 3%; between 3% and 10%, 9%, 8%, 7%, 6%, 5%, or 4%; between 4% and 10%, 9%, 8%, 7%, 6%, or 5%; between 5% and 10%, 9%, 8%, 7%, or 6%; between 6% and 10%, 9%, 8%, or 7%; between 7% and 10%, 9%, or 8%; between 8% and 10%, or 9%; or between 9% and 10% by weight of all other components.- 27 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086

[0090] In most aspects, the dietary products further comprise water. In some such aspects, the dietary products comprise between 2% and 95%, 85%, 75%, 65%, 55%, 45%, 35%, 25%, 15%, 10%, or 5%; between 5% and 95%, 85%, 75%, 65%, 55%, 45%, 35%, 25%, 15%, or 10%; between 10% and 95%, 85%, 75%, 65%, 55%, 45%, 35%, 25%, or 15%; between 15% and 95%, 85%, 75%, 65%, 55%, 45%, 35%, or 25%; between 25% and 95%, 85%, 75%, 65%, 55%, 45%, or 35%; between 35% and 95%, 85%, 75%, 65%, 55%, or 45%; between 45% and 95%, 85%, 75%, 65%, or 55%; between 55% and 95%, 85%, 75%, or 65%; between 65% and 95%, 85%, or 75%; between 75% and 95%, or 85%; or between 85% and 95% by weight of water.E. Attributes

[0091] The dietary products provided herein have one or more desirable attributes.

[0092] In some aspects, the desirable attributes are desirable colors. The color of a composition can be evaluated by a panel of expert human subjects. Alternatively, the color of a composition can be described, for example, by measuring its spectral absorption pattern using a spectrophotometer or colorimeter. Variables that can be titrated to modulate the color of the dietary products provided herein include but are not limited to amounts and / or types of coloring agents, amounts and / or types of color stabilizers, amounts and / or types of color modifiers, and micelle characteristics (e.g., compositions, sizes, densities). In some aspects, the dietary products have a L* color value of between 80 and 95, an a* color value of between -5 and 0.5, and a b* color value of between 4 and 10. In some aspects, the dietary products comprise fluorescent proteins selected from the group consisting of green fluorescent protein (GFP), blue fluorescent protein (BFP), cyan fluorescent protein (CFP), yellow fluorescent protein (YFP), orange fluorescent protein (OFP), red fluorescent protein (RFP), and derivatives thereof.

[0093] In some aspects, the desirable attributes are desirable tastes. The taste of a composition can be evaluated by a panel of expert human subjects. Alternatively, the taste of a composition can be described using automated devices (e.g., iNSENT TS-5000Z Taste Testing System (Higuchi USA Inc., Japan), Astree tongue system (Alpha MOS America, Hanover, Md.)). Variables that can be titrated to modulate the taste of the dietary products provided herein include but are not limited to amounts and / or types taste agents, amounts and / or types taste stabilizers, amounts and / or types taste modifiers, and amounts and / or types of taste blockers.

[0094] In some aspects, the desirable attributes are desirable textures (i.e., mechanical characteristics that are correlated with sensory perceptions; non-limiting examples are mouthfeel, fattiness, creaminess, viscosity, homogenization, richness, thickness, G' storage- 28 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086modules value). The texture of a composition can be evaluated by a panel of expert human subjects. Alternatively, the texture of a composition can be described by dynamic oscillation rheology, viscosity analysis, flow analysis, melt analysis, sheer stress analysis, storage modulus analysis, and texture profile analysis using a texture analyzer. Variables that can be titrated to modulate the texture of the dietary products provided herein include but are not limited to composition (e.g., types and amounts of amino acids and proteins, types and / or amounts of lipids, types and / or amounts of carbohydrates, types and / or amounts of micelles, types and / or amounts of hydrocolloids, types and / or amounts of stabilizers, types and / or amounts of emulsifiers), micelle characteristics (e.g., composition, size, density), pH, water activity, and production process conditions (e.g., temperature, hold time at temperature, pH, amount of shear applied, types of starter cultures, post fermentation treatments, and ion strengths).

[0095] In some aspects, the desirable attributes are desirable digestibility. The digestibility of a composition can be described by incubating the composition in the presence of digestive enzymes (e.g., porcine pepsin) and under conditions that prevail in the digestive tract (e.g., in presence of simulated gastric fluid with acidic pH). Variables that can be titrated to modulate the digestibility of the dietary products provided herein include but are not limited to the content of proteins comprising target sites for digestive enzymes, thermal treatment, and content of anti-nutritional factors.

[0096] In some aspects, the desirable attributes are desirable nutrient contents. In some aspects, the desirable nutrient contents are nutrient contents that are different from the nutrient contents of obtained from diet (e.g., better amino acid content, better mineral balance). Nutrient content can be defined by protein content, types and / or amounts of amino acids, types and / or amounts of lipids, types and / or amounts of carbohydrates, types and / or amounts of minerals, types and / or amounts of vitamins, types and / or amounts of bioactive compounds, types and / or amounts of micronutrients, types and / or amounts of macronutrients, types and / or amounts of lactic acid bacteria, PDCAAS score, etc. The nutrient content of a composition can be determined by analytical methods (e.g., AOAC International reference methods AOAC 990.03 and AOAC 992.15, electrophoresis (e.g., SDS-PAGE), liquid column chromatography, immunochemical tests, or on-chip electrophoresis (e.g., using the Agilent Protein 80 kit and the Agilent 2100 Bioanalyzer) for determination of type and / or content of proteins and amino acids; AOAC International reference method AOAC 954.02 for determination of type and / or content of lipids), or it can be derived from the nutrient contents of the ingredients of a dietary product. In some aspects, the dietary products provided herein comprise at least 0.5%, 0.6%, 0.7%, or 0.8%; between 0.5% and 2.5%, 2%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, or 0.6%; between 0.6% and 2.5%, 2%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%,- 29 - 301447048Attorney Docket No. UTSDP4183WO2- 10013750860.9%, 0.8%, or 0.7%; between 0.7% and 2.5%, 2%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, or 0.8%; between 0.8% and 2.5%, 2%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, or 0.9%; between 0.9% and 2.5%, 2%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, or 1.0%; between 1.0% and 2.5%, 2%, 1.5%, 1.4%, 1.3%, 1.2%, or 1.1%; between 1.1% and 2.5%, 2%, 1.5%, 1.4%, 1.3%, or 1.2%; between 1.2% and 2.5%, 2%, 1.5%, 1.4%, or 1.3%; between 1.3% and 2.5%, 2%, 1.5%, or 1.4%; between 1.4% and 2.5%, 2%, or 1.5%; between 1.5% and 2.5%, or 2%; or between 2% and 2.5% by weight of branched amino acids. In some aspects, the dietary products have PDCAAS scores of at least 80; at least 85; at least 90; at least 100; at least 105; at least 110; at least 115; at least 120; at least 125; between 80 and 150, 140, 130, 120, 110, 100, or 90; between 90 and 150, 140, 130, 120, 110, or 100; between 100 and 150, 140, 130, 120, or 110; between 110 and 150, 140, 130, or 120; between 120 and 150, 140, or 130; between 130 and 150, or 140; or between 140 and 150. In some aspects, the dietary products comprise less than 4% by weight of lactose. In some aspects, the dietary products comprise less than 2% by weight of monosaccharides. In some aspects, the dietary products comprise less than 2% by weight of disaccharides. In some aspects, the dietary products compared to dietary products have a higher content of at least one component selected from the group consisting of calcium, phosphate, B complex vitamins, vitamin A, vitamin D, vitamin E, and vitamin K.

[0097] In some aspects, the desirable attributes are desirable shelf-lives. The shelf life of a composition can be described by repeatedly measuring key attributes of the composition over the course of storage. Variables that can be titrated to modulate the shelf life of a composition include but are not limited to types and / or amounts of proteases, microbial load, solid concentration, water activity, redox potential, salt concentration, pH, natural preservative content, and humidity. In some aspects, the dietary products provided herein are stable at temperatures of 4 C or below for at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 10 days, at least 15 days, at least 20 days, at least 30 days, at least 40 days at least 50 days, at least 60 days, at least 70 days, at least 80 days, at least 90 days, between 4 days and 25 days, between 8 days and 20 days, between 15 days and 30 days, or between 40 days and 90 days. In some aspects, the dietary products are stable at ambient temperature for at least 2 months; at least 3 months; at least 4 months; at least 5 months; at least 6 months; between 2 months and 12 months, 10 months, 8 months, 6 months, or 4 months; between 4 months and 12 months, 10 months, 8 months, or 6 months; between 6 months and 12 months, 10 months, or 8 months; between 8 months and 12 months, or 10 months; or between 10 months and 12 months.

[0098] In some aspects, the desirable attributes are desirable hunger and / or satiety regulation. The hunger and / or satiety regulation of a composition can be evaluated by a panel- 30 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086of expert human subjects. Variables that can be titrated to modulate the hunger and / or satiety regulation of the dietary products provided herein include but are not limited to nutrient content (e.g., types and / or amounts of protein, types and / or amounts of lipid, types and / or amounts of carbohydrate), digestibility, fiber content, and glycemic response.

[0099] In some aspects, the desirable attributes are desirable use versatility (i.e., ability to use the dietary products in a variety of manners and / or to derive a diversity of other compositions from the dietary product). Variables that can be titrated to modulate the use versatilities of a composition provided herein include but are not limited to types and / or amounts of proteins, types and / or amounts of carbohydrates, types and / or amounts of lipids, hydrocolloid contents, process conditions (e.g., temperature, hold time, pH, shear amount), membrane processing, and ion strengths.

[0100] In some aspects, the desirable attributes is texture (e.g., creaminess, richness, thickness, smoothness, hardness, crystallization, shape retention). The texture of a composition can be evaluated by panels of expert human subjects, melt tests, shape retention tests, ice crystal counting, altitude stability testing, and overrun capacity analysis. Variables that can be titrated to modulate the texture of the dietary products provided herein include but are not limited to amounts and / or types of protein, amounts and / or types of lipids, amounts and / or types of carbohydrates, moisture content, pH, amounts and / or types of high and low molecular weight components that can affect freezing points, hydrocolloid contents, emulsified contents, method of manufacture (e.g., temperature of pasteurization, hold time, homogenization conditions, cooling / aging rate, conditions and / or methods of freezing, hardening), and storage conditions.

[0101] In some such aspects, the desirable attributes are not requiring pasteurization or cold shipping (e.g., due to possibility of sterilizing components individually prior to combining). Variables that can be titrated to modulate the pasteurization or cold shipping requirement of dietary products provided herein include but are not limited to amounts and / or types of bacteria in the composition.

[0102] In some aspects, the desirable attributes persist over storing the dietary products provided herein at suitable storage conditions. In some such aspects, the suitable storage conditions include storage at temperatures of less than 15° C. In some aspects, the desirable attributes persist over one or more cycles of freezing and thawing. In some such aspects, the one or more cycles of freezing and thawing are 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, or more than 5 cycles of freezing and thawing.

[0103] In some aspects, the dietary product may be in any form suitable for consumption. In some aspects, the dietary product is in the form of a powder, a gel, a solution, an emulsion, a- 31 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086suspension, a paste, a solid, a pellet, a liquid, a liquid concentrate, a powder which may be reconstituted, a shake, a concentrate, a pill, a bar, a tablet, a capsule, injectable solution, or a ready-to-use product.III. Kits and dietary regimens

[0104] In some aspects, the current disclosure also encompasses dietary regimens or kits comprising prepackaged meals and instructions for use. Prepackaged meal regimens offer a convenient and structured way to manage daily nutrition, particularly for individuals with busy schedules, specific dietary goals (for example, intake of a diet essentially devoid of tryptophan, or low tryptophan diets) or health-related needs. These regimens typically include a variety of ready-to-eat or easy-to-prepare meals that are portion-controlled and balanced in terms of macronutrients (proteins, carbohydrates, and fats). They are designed to simplify meal planning and help individuals adhere to specific dietary requirements, such as weight loss, muscle gain, or managing conditions like diabetes or hypertension. In some aspects, a prepackaged meal regimen of the current disclosure may comprise one or more meals which are essentially devoid of tryptophan. In some aspects, the prepackaged meal regimen may comprise one or more daily meals, for example breakfast, lunch, dinner, one or more snacks, or any combination thereof. In some aspects, the prepackaged meal regimen may comprise uncooked, cooked, or partially cooked meals, with instructions to cook, heat, re-heat the meal. Many prepackaged meal regimens are available in different formats, including frozen, refrigerated, or shelf-stable options, and they often come with detailed nutritional information and calorie counts to help users stay on track with their goals.IV. Methods of treating

[0105] In some aspects, the current disclosure encompasses a method for treating or preventing obesity or a metabolic disease comprising a controlled diet intake by the subject, wherein the diet is substantially devoid of tryptophan. Tryptophan restriction may be implemented by providing the subject with dietary instructions on reducing or eliminating daily intake of tryptophan containing diets. Alternatively, the subject may be provided with prepackaged meals (e.g., breakfast meals, lunch meals, dinner meals, or snacks) that do not contain or have low amounts of tryptophan. In certain aspects, the diet reduces the subject's daily intake of foods containing tryptophan by at least 20% to 100%, including any percent within this range, such as 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, or 100%. Preferably, the diet provides other nutrients at levels in accordance with United States Recommended Daily Allowances (USRDA) guidelines. In some aspects, replacement or substantial replacement of consumption of usual sources of amino acids such as protein with the disclosed dietary product or diet regimen will yield a diet substantially- 32 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086devoid of tryptophan. In some aspects, the controlled diet may provide therapeutic benefits to a subject suffering from a disease or disorder.

[0106] In some aspects, the subject is put on a protein-free or low-protein diet and further administered an amino acid-containing supplement comprising all of the essential amino acids (i.e., histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, and valine), except tryptophan. The amino acid-containing supplement may further comprise one or more nonessential amino acids selected from the group consisting of alanine, arginine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, and tyrosine. In some aspects, the subject is administered a dietary product as disclosed herein, as the amino acid supplement. In some aspects, the subject may be provided a dietary product as disclosed herein to reduce the amount of tryptophan in the diet. In some aspects, the dietary product may account for at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or more of the diet of the subject.

[0107] In some aspects, the subject is administered the controlled diet is for less than, more than or about 6 months, 5 months, 4 months, 3 months, 2 months, 1 month, 3 weeks, or 2 weeks.A. Indications1. Obesity

[0108] In some aspects, the condition, disease or disorder is obesity and conditions, diseases or disorders that are associated with or related to obesity. Non-limiting examples of obesity and obesity related conditions include symptomatic obesity, simple obesity, childhood obesity, morbid obesity, and abdominal obesity (central obesity characterized by abdominal adiposity). Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing syndrome, hypothyroidism, insulinoma, obese type II diabetes, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, hereditary obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), and drug-induced obesity (e.g., steroid, phenothiazine, insulin, sulfonylurea agent, or p-blocker-induced obesity).

[0109] In some aspects, the condition, disease or disorder is associated with obesity. Examples of such conditions, diseases or disorders include, without limitation, glucose tolerance disorders, diabetes (e.g., type 2 diabetes, obese diabetes), lipid metabolism abnormality, hyperlipidemia, hypertension, cardiac failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., brain thrombosis, transient cerebral ischemic attack), bone or articular disease (e.g., knee osteoarthritis, hip osteoarthritis, spondylitis deformans, lumbago), sleep apnea syndrome, obesity hypoventilation syndrome - 33 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086(Pickwickian syndrome), menstrual disorder (e.g., abnormal menstrual cycle, abnormality of menstrual flow and cycle, amenorrhea, abnormal catamenial symptom), visceral obesity syndrome, and metabolic syndrome. In some aspects, the chemical compound and pharmaceutical compositions described herein can be used to treat subjects exhibiting symptoms of both obesity and insulin deficiency.2. Diabetes

[0110] In some aspects, the condition, disease or disorder is diabetes. Non-limiting examples of diabetes include type 1 diabetes mellitus, type 2 diabetes mellitus (e.g., diet-treated type 2-diabetes, sulfonylurea-treated type 2-diabetes, a far-advanced stage type 2-diabetes, longterm insulin-treated type 2-diabetes), diabetes mellitus (e.g., non-insulin-dependent diabetes mellitus, insulin-dependent diabetes mellitus), gestational diabetes, obese diabetes, autoimmune diabetes, and borderline type diabetes. In some aspects, the condition, disease or disorder is type 2 diabetes mellitus (e.g., diet-treated type 2-diabetes, sulfonylurea-treated type 2-diabetes, a far-advanced stage type 2-diabetes, long-term insulin-treated type 2-diabetes).

[0111] In some aspects, compositions and methods for treating a subject with a condition, disease, or disorder (e.g., type 2 diabetes mellitus) described herein reduce fasting plasma glucose levels. In some aspects, compositions and methods for treating a subject with a condition, disease, or disorder (e.g., type 2 diabetes mellitus) described herein reduce nonfasting plasma glucose levels. In some aspects, compositions and methods for treating a subject with a condition, disease, or disorder (e.g., type 2 diabetes mellitus) described herein reduce HbA1c levels. In some aspects, compositions and methods for treating a subject with a condition, disease, or disorder (e.g., type 2 diabetes mellitus) described herein reduce glucagon levels. In some aspects, compositions and methods for treating a subject with a condition, disease, or disorder (e.g., type 2 diabetes mellitus) described herein increase insulin levels. In some aspects, compositions and methods for treating a subject with a condition, disease, or disorder (e.g., type 2 diabetes mellitus) described herein reduce BMI.

[0112] In some aspects, a reduction in fasting plasma glucose levels of about 5% to about 95% indicates treatment of type 2 diabetes mellitus. In some aspects, a reduction in fasting plasma glucose levels of about 15% to about 80% indicates treatment of type 2 diabetes mellitus. In some aspects, a reduction in fasting plasma glucose levels of about 25% to about 60% indicates treatment of type 2 diabetes mellitus. In some aspects, a reduction in fasting plasma glucose levels to about or below 126 mg / dL, about or below 110 mg / dL, or about or below 90 mg / dL indicates treatment of the type 2 diabetes mellitus.- 34 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086

[0113] In some aspects, a reduction in non-fasting plasma glucose levels of about 5% to about 95% indicates treatment of type 2 diabetes mellitus. In some aspects, a reduction in nonfasting plasma glucose levels of about 15% to about 80% indicates treatment of type 2 diabetes mellitus. In some aspects, a reduction in non-fasting plasma glucose levels of about 25% to about 60% indicates treatment of type 2 diabetes mellitus. In some aspects, a reduction in non-fasting plasma glucose levels to about or below 200 mg / dL, about or below 150 mg / dL, or about or below 130 mg / dL indicates treatment of type 2 diabetes mellitus.

[0114] In some aspects, a reduction in HbA1c levels of about 5% to about 95% indicates treatment of type 2 diabetes mellitus. In some aspects, a reduction in HbA1c levels of about 15% to about 80% indicates treatment of type 2 diabetes mellitus. In some aspects, a reduction in HbA1c levels of about 25% to about 60% indicates treatment of type 2 diabetes mellitus. In some aspects, reduction in HbA1c levels to about or below 6.5%, about or below 6.0%, or about or below 5.0% indicates treatment of type 2 diabetes mellitus.

[0115] In some aspects, a reduction in glucagon levels of about 5% to about 95% indicates treatment of type 2 diabetes mellitus. In some aspects, a reduction in glucagon levels of about 15% to about 80% indicates treatment of type 2 diabetes mellitus. In some aspects, a reduction in glucagon levels of about 25% to about 60% indicates treatment of type 2 diabetes mellitus. In some aspects, an increase in insulin levels of about 5% to about 95% indicates treatment of type 2 diabetes mellitus. In some aspects, an increase in insulin levels of about 15% to about 80% indicates treatment of type 2 diabetes mellitus. In some aspects, an increase in insulin levels of about 25% to about 60% indicates treatment of type 2 diabetes mellitus.

[0116] In some aspects, a reduction in BMI of about 5% to about 95% indicates treatment of type 2 diabetes mellitus. In some aspects, a reduction in BMI of about 15% to about 80% indicates treatment of the type 2 diabetes mellitus. In some aspects, a reduction in BMI of about 25% to about 60% indicates treatment of type 2 diabetes mellitus. In some aspects, a reduction in BMI of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% indicates treatment of type 2 diabetes mellitus. In some aspects, a reduction in BMI to about or below 40, about or below 30, or about or below 20 indicates treatment of type 2 diabetes mellitus.

[0117] In some aspects, the condition, disease or disorder is associated with diabetes (e.g., a complication of diabetes). Non-limiting examples of disorders associated with diabetes include obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataract,- 35 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious disease (e.g., respiratory infection, urinary tract infection, gastrointestinal infection, dermal soft tissue infections, inferior limb infection), diabetic gangrene, xerostomia, hypacusis, cerebrovascular disorder, diabetic cachexia, delayed wound healing, diabetic dyslipidemia peripheral blood circulation disorder, cardiovascular risk factors, (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension, and risk factors related to unmanaged cholesterol and / or lipid levels, and / or inflammation), NASH, bone fracture, and cognitive dysfunction

[0118] Other non-limiting examples of disorders related to diabetes include pre-diabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, high LDL-cholesterolemia, low HDL-cholesterolemia, postprandial hyperlipemia), metabolic syndrome (e.g., metabolic disorder where activation of GLP-1R is beneficial, metabolic syndrome X), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[0119] In some aspects, the condition, disease or disorder is diabetes and obesity (diabesity). In some aspects, the compounds described herein are also useful in improving the therapeutic effectiveness of metformin.3. Disorders of Metabolically Important Tissues

[0120] In some aspects, the condition, disease or disorder is a disorder of a metabolically important tissue. Non-limiting examples of metabolically important tissues include liver, fat, pancreas, kidney, and gut.

[0121] In some aspects, the condition, disease or disorder is a fatty liver disease. Fatty liver diseases include, but are not limited to, non-alcoholic fatty acid liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease resulting from hepatitis, fatty liver disease resulting from obesity, fatty liver disease resulting from diabetes, fatty liver disease resulting from insulin resistance, fatty liver disease resulting from hypertriglyceridemia, Abetalipoproteinemia, glycogen storage diseases, Weber-Christian disease, Wolman’s disease, acute fatty liver of pregnancy, and lipodystrophy.

[0122] Other non-limiting examples of disorders in metabolically important tissues include joint disorders (e.g., osteoarthritis, secondary osteoarthritis), steatosis (e.g. in the liver); gall stones; gallbladder disorders; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; bone disorder characterized by altered bone metabolism, such as osteoporosis, including postmenopausal osteoporosis, poor bone strength, osteopenia, Paget's disease, osteolytic metastasis in cancer subjects, osteodistrophy in liver disease and the altered bone metabolism caused by renal failure or haemodialysis, bone fracture, bone surgery, aging, pregnancy, protection against bone fractures, and malnutrition polycystic ovary syndrome; renal disease- 36 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086(e.g., chronic renal failure, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease); muscular dystrophy, angina pectoris, acute or chronic diarrhea, testicular dysfunction, respiratory dysfunction, frailty, sexual dysfunction (e.g., erectile dysfunction), and geriatric syndrome. In some aspects, compositions described herein can be used for treating surgical trauma by improving recovery after surgery and / or by preventing the catabolic reaction caused by surgical trauma.4. Cardiovascular and Vascular Diseases

[0123] In some aspects, the condition, disease or disorder is a cardiovascular disease. Nonlimiting examples of cardiovascular disease include congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, cardiac failure, cerebrovascular disorder (e.g., cerebral infarction), vascular dysfunction, myocardial infarction, elevated blood pressure (e.g., 130 / 85 mm Hg or higher), and prothrombotic state (exemplified by high fibrinogen or plasminogen activator inhibitor in the blood).

[0124] In some aspects, the condition, disease or disorder is related to a vascular disease. Non-limiting examples of vascular diseases include peripheral vascular disease, macrovascular complications (e.g., stroke), vascular dysfunction, peripheral artery disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disorder (e.g., cerebral infarction), pulmonary embolism, chronic venous insufficiency, critical limb ischemia, retinopathy, nephropathy, and neuropathy.5. Insulin-Related

[0125] In some aspects, the condition, disease or disorder is impaired fasting glucose (IFG), impaired fasting glycemia (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood levels of fatty acids or glycerol, a hypoglycemic condition, insulin resistant syndrome, paresthesia caused by hyperinsulinemia, hyperlipidaemia, hypercholesteremia, impaired wound healing, leptin resistance, glucose intolerance, increased fasting glucose, dyslipidemia (e.g., hyperlipidemia, atherogenic dyslipidemia characterized by high triglycerides and low HDL cholesterol), glucagonoma, hyperuricacidemia, hypoglycemia (e.g., nighttime hypoglycemia), and concomitant comatose endpoint associated with insulin.In some aspects, compositions described herein can reduce or slow down the progression of borderline type, impaired fasting glucose or impaired fasting glycemia into diabetes.- 37 - 301447048Attorney Docket No. UTSDP4183WO2- 10013750866. Autoimmune Disorders

[0126] In some aspects, the condition, disease or disorder is an autoimmune disorder. Nonlimiting examples of autoimmune disorders include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disorder is associated with immune rejection, graft versus host disease, uveitis, optic neuropathies, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis, and Graves’ disease. See, e.g., US20120148586A1. 7. Stomach and Intestine-Related Disorders

[0127] In some aspects, the condition, disease or disorder is a stomach or intestine related disorder. Non-limiting examples of these disorders include ulcers of any etiology (e.g. peptic ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, ulcers related to infections or other pathogens), digestion disorders, malabsorption, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel diseases (Crohn's disease and ulcerative colitis), celiac sprue, hypogammaglobulinemic sprue, chemotherapy and / or radiation therapy-induced mucositis and diarrhea, gastrointestinal inflammation, short bowel syndrome, colitis ulcerosa, gastric mucosal injury (e.g., gastric mucosal injury caused by aspirin), small intestinal mucosal injury, and cachexia (e.g., cancerous cachexia, tuberculous cachexia, cachexia associated with blood disease, cachexia associated with endocrine disease, cachexia associated with infectious disease, and cachexia caused by acquired immunodeficiency syndrome).8. Body Weight

[0128] In some aspects, compositions described herein can be used to reduce body weight (e.g., excess body weight), prevent body weight gain, induce weight loss, decrease body fat, or reduce food intake in a subject (e.g., a subject in need thereof). In some aspects, the weight increase in a subject may be attributed to excessive ingestion of food or unbalanced diets or may be weight increase derived from a concomitant drug (e.g., insulin sensitizers having a PPARy agonist-like action, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone and the like). In some aspects, the weight increase may be weight increase before reaching obesity or may be weight increase in an obese subject. In some aspects, the weight increase may also be medication-induced weight gain or weight gain subsequent to cessation of smoking.In some aspects, the condition, disease or disorder is an eating disorder, such as hyperphagia, binge eating, bulimia, or compulsive eating.- 38 - 301447048Attorney Docket No. UTSDP4183WO2- 10013750869. Inflammatory Diseases

[0129] In some aspects, the condition, disease or disorder is an inflammatory disorder. Nonlimiting examples of inflammatory disorders include chronic rheumatoid arthritis, spondylitis deformans, arthritis deformans, lumbago, gout, post-operational or post-traumatic inflammation, bloating, neuralgia, laryngopharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory large bowel disease), inflammation in metabolically important tissues including liver, fat, pancreas, kidney and gut, and a proinflammatory state (e.g., elevated levels of proinflammatory cytokines or markers of inflammation-like C-reactive protein in the blood).10. Hypothalamic-Pituitary Disorders

[0130] In some aspects, the condition, disease or disorder is related to the hypothalamic-pituitary-gonadal axis. For example, the condition, disease or disorder is related to the hypothalamus-pituitary-ovary axis. In another example, the condition, disease or disorder is related to the hypothalamus-pituitary-testis axis. Hypothalamic-pituitary-gonadal axis diseases include, but are not limited to, hypogonadism, polycystic ovary syndrome, hypothyroidism, hypopituitarism, sexual dysfunction, and Cushing's disease.In some aspects, the condition, disease or disorder associated with diabetes is related to the hypothalamic-pituitary-gonadal axis.11. Pulmonary Disease

[0131] In some aspects, the condition, disease or disorder is related to a pulmonary disease. Pulmonary diseases include, but are not limited to, asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnea-hypopnea syndrome, and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis, and refractory (non-reversible) asthma).

[0132] In some aspects, the condition, disease or disorder associated with diabetes is a pulmonary disease.B. Additional therapies

[0133] In some aspects, this disclosure contemplates using the disclosed methods and products in combination with additional therapy regimens.

[0134] In some aspects, the methods described herein can further include administering of a low-tryptophan diet regimen with one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more therapeutic regimens). In some aspects, the additional therapy may be administered concurrently or in tandem with the disclosed compositions.- 39 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086

[0135] In some aspects, the methods described herein include administering a composition described herein in combination with one or more of a diet therapy (e.g., dietary monitoring, diet therapy for diabetes), an exercise therapy (e.g., physical activity), blood sugar monitoring, gastric electrical stimulation (e.g., TANTALUS®), and diet modifications. In some aspects, the additional therapy may comprise administering a weight loss drug, drugs to control blood pressure, blood glucose levels, cardiovascular diseases etc. Non-limiting examples of such drugs include Semaglutide (Wegovy®), Liraglutide (Saxenda®), Tirzepatide (Zepbound®), Orlistat (Alli®, Xenical®), Phentermine-Topiramate (Qsymia®), Naltrexone-Bupropion (Contrave®), Metformin, Empagliflozin (Jardiance®), Dapagliflozin (Farxiga®), Sitagliptin (Januvia®), Insulin (Lantus®, Humalog®, Novolog®), Atorvastatin (Lipitor®), Rosuvastatin (Crestor®), Ezetimibe (Zetia®), PCSK9 inhibitors (Repatha®, Praluent®), ACE inhibitors (Lisinopril, Ramipril), Beta-blockers (Metoprolol, Carvedilol), Anticoagulants (Warfarin, Apixaban), and Aspirin (low dose for heart health).EXAMPLES

[0136] The following examples are included to demonstrate preferred aspects of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventor to function well in the practice of the present disclosure and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific aspects which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the present disclosure.Example 1: Overview

[0137] Obesity is a global problem affecting all demographics and is closely tied to severe health issues like heart disease, diabetes, and cancer. Numerous diets exist, ranging from low-energy and intermittent fasting to macronutrient-focused plans such as low-fat, low-carb, and high-protein diets, all of which primarily aim to alter macronutrient groups. Our lab is taking a different approach by focusing on manipulating the availability of single nutrients to understand their role in cancer and obesity.

[0138] The importance of single nutrient depletion is just beginning to be explored particularly in the context of cancer. Protein intake is considered a cornerstone of most dietary strategies; however, the role of individual amino acids in weight management is less understood. Notably, the deprivation of certain amino acids, which are required in large amounts by cancer cells, can inhibit cancer cell growth in vitro. Yet, complete withdrawal of dietary protein fails to significantly reduce circulating levels of most amino acids due to compensatory mechanisms- 40 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086like muscle wasting. Recent studies began exploring the efficacy of limiting single dietary components in cancer treatment, including methionine asparagine and glycine. Our own work demonstrated that tryptophan (Trp) depletion improves liver health and prevent liver cancer from arising7. Traditional dietary interventions, such as low-energy, very low-energy, and macronutrient-specific diets, often demand significant behavioral changes and caloric restriction. Despite these efforts, outcomes are frequently inconsistent, and adherence remains a significant challenge, particularly among individuals with obesity who often underestimate their caloric intake. While maintaining a consistent energy deficit is essential for long-term weight management, achieving sustained adherence to such diets is difficult for many.

[0139] To begin understanding the role of individual nutrients in whole-body homeostasis and energy balance, the inventors focused on nutrients that can be fully manipulated externally. This approach involved using isocaloric diets that reduce or remove specific essential amino acids to assess their importance for both cancer and normal physiological function. These tools allowed for the decoupling of caloric restriction and feeding behaviors from the specific contributions of each nutrient to overall homeostasis.

[0140] During studies focused on a tryptophan depleted (hereafter named "Trypt-out") diet, it was unexpectedly found that tryptophan deprivation led to a specific reduction in fat mass without affecting lean mass or food intake, prompting further investigation into its role in fat metabolism. Here, the hypothesis that the Trypt-out diet promotes efficient white fat mobilization, induces adipocyte cell death, and enhances lipid utilization, leading to sustained weight loss is tested. Additionally, the physiological effects of tryptophan depletion were compared with those of other essential amino acids to determine the relative safety and efficacy of the Trypt-out diet. Unlike conventional diets, Trypt-out does not necessitate changes in eating behavior or caloric restriction, yet it has demonstrated the ability to induce sustained weight loss. This observation suggests a potential paradigm shift in obesity treatment, offering a more accessible and sustainable strategy. Using synthetic isocaloric diets, each lacking one of the nine essential amino acids, the effects of short-term amino acid depletion on body composition were tested in mice. It was found that dietary tryptophan (Trp) depletion resulted in significant fat mass loss while preserving lean mass, likely due to Trp being the least abundant amino acid in the proteome. Administering the T rypt-out diet to males and females hyperphagic leptin knockout (KO) obese mice (ob / ob), or to mice with diet-induced obesity prevented and reverted weight gain led to significant fat mass reduction, improved glucose clearance, fatty liver without altering food intake or feeding behavior. Remarkably, Trypt-out also promoted fat loss in animals on a high-fat diet. It was discovered- 41 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086that Trypt-out, via the depletion of its metabolite indole 3 pyruvate, leads to fat mass reduction by causing ferroptosis in specifically adipocytes.Example 2: Trypt-out can drive fat loss with minimal lean mass wasting and preserved food intake in wild-type and leptin-deficient (ob / ob) mice.

[0141] To determine the effect of single amino acid restriction on body composition, wild-type C57BL / 6 (WT) mice were fed synthetic, defined isocaloric diets containing either all amino acids or lacking one of the nine essential amino acids, one at a time (FIG. 1A). Mice were maintained on these diets for 2 weeks, after which food consumption, total body weight, lean mass, and fat mass were measured using EchoMRI (FIG. 1B). A matched control diet containing all essential amino acids was used for comparison. For each amino acid removed, its weight was replaced with cellulose to maintain diet consistency. Results showed that restriction of each of the nine essential amino acids caused overall weight loss (FIG. 1B).However, diets lacking isoleucine, threonine, and phenylalanine led to a significant reduction in food intake. In contrast, the synthetic diet lacking Trp (hereafter referred to as Trypt-out) was the most effective at inducing fat loss while preserving most lean mass (FIG. 1B). Further experiments were conducted with wildtype mice fed a control diet or Trypt-out diet for 3 weeks (FIG. 1C). The results confirmed that feeding Trypt-out for 3 weeks reduced circulating Trp levels (FIG. 1D) and body weight in both males and females (FIG. 1E), without altering cumulative food intake, as measured by weighing food on the hopper for 4 days in metabolic cages (FIG. 1F). Mice fed the Trypt-out diet cleared glucose more efficiently during a glucose tolerance test (GTT) (FIG. 1G), as quantified by the area under the curve (AUG), and displayed a preferential reduction in fat mass with more modest loss of lean mass (FIG. 1H). Hematoxylin and eosin (H&E) staining of tissue sections from mice fed the Trypt-out diet demonstrated a reduction in lipid content within adipocytes of the gonadal white adipose tissue (gWAT), and to a lesser extent in inguinal white adipose tissue (iWAT) (FIG. 11). Brown adipose tissue (BAT) also showed reduced lipid content and a denser cellular organization (FIG. 11). The overall morphology and organization of liver and muscle tissues were unaltered in wild-type mice after 3 weeks of dietary Trp restriction.

[0142] To test whether Trp depletion could reverse obesity in mouse models, Trypt-out in ob / ob mice, which lack the gene encoding the hormone leptin, are hyperphagic, and typically become obese by 8-10 weeks of age (ref), were evaluated. Administering the Trypt-out diet for 4 weeks to 10-week-old ob / ob mice that were already obese (FIG. 1 J) reduced circulating Trp levels (FIG. 1K) and resulted in significant weight loss in both males and females (FIG.1L), with only modest changes in cumulative food intake (FIG. 1M). Resting glucose levels and glucose tolerance tests (GTTs) revealed a dramatic improvement in glucose clearance in obese mice fed Trypt-out (FIG. 1N). Among tissues, the weights of inguinal white adipose - 42 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086tissue (iWAT), brown adipose tissue (BAT), and liver were most markedly reduced by the Trypt-out diet in these obese mice (FIGS. 10-1 P). The absolute reduction in fat mass was substantial. Consistent with these findings, morphological changes assessed by H&E staining revealed pronounced tissue remodeling, including browning of BAT, reductions in iWAT, and loss of lipid droplets in the liver (FIG. 1Q). Both lean mass and fat mass were reduced in Trypt-out-fed mice (FIG. 1R), with a significantly greater reduction in fat mass. Notably, liver weight was dramatically decreased, and exclusion of liver weight from lean mass calculations revealed that the modest loss of lean mass was largely attributable to reduced liver mass (FIG.1S). Remarkably, reintroducing dietary tryptophan after 4 weeks of Trypt-out feeding led to weight gain; however, body weight plateaued at a lower level compared to mice continuously maintained on a Trp-containing diet (FIG. 1T).Example 3: Tryp-out can prevent and revert obesity induced by high fat diet.

[0143] To determine whether dietary Trp depletion could prevent or reverse high-fat diet-induced obesity, wild-type (WT) mice were fed either an HFD containing all essential amino acids or an HFD lacking Trp (HFD-Trypt-out) for three weeks (FIG. 2A). The HFD-Trypt-out diet caused a significant reduction in overall body weight (FIG. 2B), with only modest changes in food intake (FIG. 2C). Resting blood glucose levels and GTT responses were also improved (FIG. 2D). Weight loss was driven primarily by a reduction in fat mass, with only a modest effect on lean mass (FIG. 2E). Similar experiments performed in male C57BL / 6 and FVB mice yielded comparable results, indicating that the effects of Trp deprivation are not strain specific. FVB mice fed an HFD for 12 weeks and subsequently switched to the Trypt-out diet exhibited reduced circulating Trp levels (FIG. 2A), a marked reduction in fat mass, predominantly gWAT, and a dramatic decrease in adipocyte lipid content (FIG. 2F). Likewise, C57BL / 6 mice with diet-induced obesity (DIO) generated by 16 weeks of HFD feeding showed significant reductions in body weight and fat mass after three weeks on the Trypt-out diet (FIGS. 2G-2J).Importantly, Trypt-out-fed mice preserved normal liver function (FIG. 2K), as indicated by normal circulating levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), enzymes that enter the bloodstream when the liver is damaged. Importantly, by quantifying circulating triglycerides and cholesterol in normal mice after 3 days or 3 weeks of T rypt-out feeding, as well as in ob / ob mice and ob / ob mice fed a high-fat diet, it was found that cholesterol levels were reduced in Trypt-out-fed mice (FIGS. 2L-2M). Metabolic cage analyses revealed that mice fed the Trypt-out diet exhibited a reduced respiratory exchange ratio (RER), calculated from oxygen consumption (VO2) and carbon dioxide production (VCO2), indicating a shift toward fatty acid p-oxidation as the primary energy source (FIG. 2N).Heat production and locomotor activity were not consistently altered, and continuous monitoring across light and dark cycles revealed no major behavioral changes or disruptions- 43 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086in circadian rhythm. Consistent with improved metabolic status, Trypt-out-fed mice displayed reduced circulating insulin and leptin levels after three weeks compared with control diet-fed mice (FIG. 20). In contrast, other feeding-related hormones, including ghrelin, glucagon, and GLP-1, were not consistently altered. Together, these data demonstrated that dietary tryptophan deprivation is sufficient to prevent high-fat diet-induced weight gain and to reverse established obesity, even in the presence of excess dietary fat or sucrose, without reducing food intake.Example 4: Trypt-out-driven fat loss is not caused by inhibition of translation or depletion of Trp metabolites.

[0144] To investigate the mechanisms by which Trypt-out affects body homeostasis, the impact of feeding the Trypt-out diet for three weeks on global protein synthesis was first examined across mouse tissues (FIG.3A). Protein synthesis was assessed by puromycylation1 2, which relies on the incorporation of puromycin into nascent peptides followed by detection using anti-puromycin Western blotting (FIG. 3B). To assess the immediate and direct effects of Trp depletion on translation, puromycylation assays were performed in cultured adipocytes and hepatocytes subjected to short-term Trp starvation. Removal of Trp from the culture medium of H2-35 hepatocytes had no detectable effect on global translation rates (FIG. 3C).Similarly, in 3T3-L1 fibroblasts, either undifferentiated or differentiated into adipocytes (FIG.3D), altering Trp concentrations from 0 to 75 pM, corresponding to the concentration present in standard DMEM, did not affect protein synthesis in either cell type (FIG. 3E). Importantly, Trp removal did not compromise adipocyte identity, as differentiated 3T3-L1 cells-maintained expression of adipocyte markers under Trp-deficient conditions (FIG. 3F). To study the impact of Trypt-out on translation in vivo, mice were administered O-propargyl-puromycin (OPP), a puromycin analog with enhanced permeability that is rapidly incorporated into elongating polypeptides, and tissues were harvested three hours after tail vein injection. Given the pronounced fat loss observed in Trypt-out-fed mice, adipose tissues including brown adipose tissue (BAT), gonadal white adipose tissue (gWAT), and inguinal white adipose tissue (iWAT), as well as liver, were analyzed using anti-puromycin immunoblotting (FIG. 3G). The liver was included because it represents both a central site of Trp metabolism and a major metabolic hub (FIG. 2B). These analyses revealed no significant reduction in protein synthesis following three weeks of dietary T rp depletion (FIG. 3H). These findings are consistent with the previous observations that both liver cancer and normal liver maintain protein synthesis rates when provided a Trp-deficient diet3. Indeed Trypt-out caused no dramatic effects on the levels of amino acids in the liver (FIG. 3I). Together, these data indicated that short-term Trp depletion does not impair global protein synthesis or adipocyte identity in vivo or in vitro.- 44 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086

[0145] Considering that Trp is the largest essential amino acid and can give rise to multiple bioactive metabolites, whether Trp-derived metabolites contribute to the regulation of lipid homeostasis was investigated. Trp is metabolized through several pathways, including the serotonin, kynurenine (Kyn), and indole-3-pyruvate (I3P) pathways (FIG. 3J)3, all of which were markedly reduced in the circulation of Trypt-out-fed mice (Figure..), in addition to microbiome-derived Trp metabolites and acetyl CoA. This interest arose from the observation that both Trp and its downstream metabolites are similarly depleted in mice fed the Trypt-out diet (FIGS. 3J-3M). Trypt-out-fed mice exhibited lower circulating levels of tryptophan metabolites, indicating that Trypt-out inhibits the entire tryptophan metabolic pathway (FIG.3K). In addition, Trp-derived metabolites produced by the gut microbiome can signal to the host and influence metabolic homeostasis.

[0146] Daily intraperitoneal injections of I3P, Kyn, or 5-hydroxytryptophan (5-HTP), administered either concomitantly with the Trypt-out diet (FIG. 3L) or after initiation of Trypt-out feeding, did not rescue the weight or fat loss induced by Trypt-out. To further determine whether microbiome-derived Trp metabolites contribute to Trypt-out-induced fat loss, the gut microbiome was depleted by administering drinking water containing penicillin and streptomycin prior to and throughout the experiment. Microbiome depletion did not alter either the rate or magnitude of weight loss induced by the Trypt-out diet (FIG. 3M), indicating that microbiome-derived metabolites are not the primary drivers of this phenotype. Finally, given that I3P has been reported to inhibit ferroptosis in cultured HeLa cells4and that Trypt-out reduces glutathione levels in adipose tissue of ob / ob mice (FIG. 3K), increases levels of peroxidized PRDX3, decreased glutathione (FIG. 3N) and promotes lipid peroxidation in adipocytes (FIG. 30), the effect of Trp starvation on adipocyte viability was examined. Trp deprivation modestly reduced the viability of both differentiated and undifferentiated adipocytes, and this reduction was rescued to a similar extent by either ferrostatin-1 or I3P (FIGS. 3P), suggesting that adipocytes may undergo ferroptosis upon Trp starvation. While ferroptosis markers were elevated in adipose tissue, these changes were not observed in liver tissue, indicating a preferential effect on adipocytes. However, daily intraperitoneal administration of liproxstatin-1 to Trp-starved leptin-deficient mice fed the Trypt-out diet did not rescue fat loss (FIG. 3Q), which indicated that although ferroptosis may contribute to the phenotype, it is not the sole driver of fat loss in vivo.Example 5: Providing additional energy sources, such as a high-fat diet (HFD) or sucrose, does not rescue the weight loss induced by Trypt-out.

[0147] Trp is a ketogenic amino acid capable of generating acetyl-CoA (FIG. 4A), which can fuel both gluconeogenesis and lipogenesis. Consistent with this, Trypt-out feeding caused a preferential reduction in 2-aminoadipate, the intermediate produced from tryptophan and - 45 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086lysine during acetyl-CoA and lipid synthesis from amino acids (FIG. 4B). Importantly, lysine levels and its downstream product pipecolate were unchanged in Trypt-out-fed mice, indicating that the reduction in 2-aminoadipate specifically reflects Trp starvation (FIG. 4B).Next, whether providing alternative sources of acetyl CoA could compensate for Trp loss in ob / ob mice was evaluated, ob / ob mice were provided the Trypt-out diet and given access to drinking water supplemented with either sucrose or stevia as a control (FIG. 4C) for three weeks. Mice provided sucrose containing water lost as much weight as mice given stevia containing water, indicating that sucrose cannot compensate for the loss of dietary Trp (FIGS.4D-4E). Both groups consumed less solid food due to the availability of sweetened water (FIG.4F). In agreement with the equivalent weight loss observed between the groups, resting glucose levels and glucose tolerance were unaltered (FIG.4G). Fat mass and lean mass were also comparable between groups.

[0148] To determine whether a HFD could compensate for the lack of dietary Trp, ob / ob mice were provided with either an HFD or an HFD Trypt-out diet for four weeks (FIG. 4H). Mice fed the HFD gained additional weight, whereas mice fed the HFD Trypt-out diet lost weight (FIGS.4I-4J), despite HFD Trypt out fed mice consuming more food than mice fed the HFD alone (FIG. 4K). Remarkably, mice fed the HFD Trypt-out diet displayed improved resting glucose levels and glucose clearance (FIG. 4L), accompanied by dramatic reductions in fat mass and liverweight. Similar results were obtained in wild-type mice fed either an HFD or an HFDTrypt-out diet (FIG. 4M). Mice fed the HFD Trypt-out diet lost weight with only minor changes in food intake (FIG. 4N), driven predominantly by fat mass loss (FIGS. 4O-4Q), and exhibited improved glucose tolerance (FIG. 4Q). In line with these results dietary Trp depletion prevented obesity in ob / ob mice when initiated prior to disease onset, ob / ob mice were placed on the Trypt-out diet starting at 6 weeks of age, before the development of overt obesity, and maintained for four weeks (FIG.4R). This intervention effectively prevented weight gain (FIGS.4S-4T). While control mice fed a Trp-containing diet gained weight during this period, Trypt-out-fed mice lost weight. Both lean and fat mass were reduced, with fat mass loss being more pronounced. Importantly, the modest reduction in lean mass was largely attributable to decreased liver weight (FIG. 4U). These changes occurred without significant alterations in food intake, and food efficiency remained unchanged (FIG. 4U). Metabolic improvements accompanied the changes in body composition. Resting glucose levels and glucose tolerance, assessed by glucose tolerance testing (GTT), were significantly improved in Trypt-out-fed mice (FIG. 4V). Consistent with these findings, the weights of white adipose tissue and liver were all markedly reduced. Histological analysis confirmed these effects, revealing smaller lipid droplets in iWAT, gWAT, as well as a striking reduction in hepatic lipid accumulation. In summary these results demonstrated that Trypt-out leads to fat loss even in the presence of- 46 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086high fat or high sugar diets and this weight loss occurs without changes in food consumption and activity levels.Example 6: Try pt-out can reshape the hepatic transcriptional landscape to prevent lipid biosynthesis.

[0149] To begin dissecting the molecular effects of the Trypt-out diet on adult tissues, RNA-seq was performed to examine transcriptional alterations in iWAT, gWAT, BAT, liver, and skeletal muscle (quadriceps) (FIG. 5A). Using a threshold of Log2FC > 1.0 and P < 0.05, it was observed that muscle tissue exhibited 77 upregulated and 112 downregulated genes. iWAT showed 36 upregulated and 26 downregulated genes. BAT displayed the most extensive response, with 2,200 genes upregulated and 2,138 downregulated. The liver showed 240 upregulated and 466 downregulated genes. Importantly, gene ontology analysis revealed that the muscle transcriptome showed downregulation of pathways related to protein digestion and amino acid metabolism, alongside upregulation of ribosome biogenesis and mTOR signaling pathways (FIG. 5B). In contrast, metabolic tissues such as iWAT showed only modest transcriptional changes (FIG. 5C), whereas the liver exhibited broad alterations. Notably, all tissues displayed downregulation of lipid metabolism genes and upregulation of ribosome biogenesis and translation-associated genes (FIGS. 5A-5D), with the most pronounced effects occurring in the liver, consistent with its central metabolic role. Importantly, liver proteomics confirmed a robust induction of ribosome biogenesis (FIGS. 5E-5F), including structural ribosomal components, tRNA-charging enzymes, and translational machinery (FIG.5G). Given that ribosome biogenesis is one of the most energetically demanding cellular processes, this marked induction was interpreted as a futile ATP-consuming cycle in Trypt-out-fed mice, diverting energy away from lipid synthesis and thereby contributing to fat loss.

[0150] Importantly, the proteomic analysis revealed that only a small subset of proteins was selectively downregulated at the protein level without corresponding decreases in RNA abundance in the liver (FIG. 5H-5I). Among the most significantly affected were key lipogenic enzymes, including FASN (30 T rp residues), ACLY (11 Trp), and ACACA (27 T rp). These data suggest that Trypt-out preferentially targets proteins with unusually high tryptophan content, which are relatively rare. These findings were validated by western blotting, which confirmed that expression of lipid biosynthetic enzymes was markedly reduced by Trypt-out in WT livers (FIG. 5J) and ob / ob livers (FIG. 5K), while glycolytic enzymes were unaffected (FIG. 5L).These effects persisted even under high-fat diet feeding (FIG. 5M) and were observed following short-term Trypt-out, indicating that they are drivers rather than consequences of fat loss (FIG. 5N). Importantly, daily injection of short peptides containing Trp was sufficient to restore lipogenic enzyme levels prior to weight changes, demonstrating that the effects of Trypt-out on these enzymes contribute directly to the phenotype (FIG. 50). Consistent with - 47 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086this, metabolomic analyses revealed a clear reduction in lipid content in both iWAT and gWAT (FIGS. 5P-5Q)

[0151] The results demonstrated that although Trypt-out reduced fat levels and 2-aminoadipate, a precursor of acetyl-CoA, it caused an accumulation of citrate, fumarate, and malate, suggesting a rerouting of carbons into the TCA cycle to generate ATP rather than fat (FIGS. 5R-5S). Using bomb calorimetry, it was further confirmed that Trypt-out-fed mice did not lose calories through malabsorption or increased fat content in feces (FIG. 5T). Moreover, metabolomic analysis revealed minimal changes in the nutrient composition of feces from Trypt-out-fed mice compared with controls (FIG. 5U). This supports the notion that obese mice have sufficient circulating citrate to supply substrates for lipid biosynthesis; however, the Trypt-out diet induces physiological changes that mechanistically prevent fat accumulation in the liver. This effect may be linked to reduced expression of key enzymes involved in lipid synthesis.Example 7: In the absence of Trp, FASN can be degraded by the E3 ligase HRD1.

[0152] Given that FASN protein levels were reduced without corresponding changes in mRNA, it was inferred that FASN and potentially other lipid synthesis enzymes are degraded under Trypt-out conditions. To test this, primary mouse hepatocytes were cultured overnight in Trp-free DM EM and then transferred them to media with or without Trp for 8 hours. FASN expression was induced in the presence of Trp; importantly, FASN levels were elevated in Trp-free media upon treatment with the proteasome inhibitor MG132 (FIG. 6A). Other lipogenic enzymes were not affected. FASN contains 30 tryptophan residues, and it was considered that this unusually high T rp content within a large (-200 kDa) enzyme could render its translation particularly sensitive to Trp availability. To test whether FASN preferentially incorporates Trp, primary mouse hepatocytes were cultured in the presence of 13C-Trp by passaging cells for 7 days in media containing 13C-Trp as the sole Trp source (FIG. 6B). LC-MS / MS analysis revealed that nearly 100% of free intracellular Trp extracted with methanol, as well as Trp present in the media, was 13C-labeled (FIG. 6C). Remarkably, at the same time point, only -10% of Trp-containing peptides in cellular proteins incorporated13C-Trp, with -90% remaining 12C-labeled, indicating extensive recycling of pre-existing Trp within cellular protein pools. Among the proteins that incorporated 13C-Trp, FASN ranked at the top, together with ACLY and ACACA (FIGS. 6D-6E). These findings demonstrated that enzymes involved in de novo lipid biosynthesis are disproportionately dependent on newly available Trp and therefore uniquely vulnerable to Trp depletion.

[0153] Loss of FASN is expected to deplete intracellular lipid pools, a condition known to perturb ER membrane homeostasis and induce ER stress. Consistent with this model, Trypt-- 48 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086out triggered activation of the unfolded protein response, as evidenced by upregulation of ATF6- and ATF4-dependent target genes, including CHOP and BIP (FIGS. 6F-6I). Moreover, the UPR-regulated ERAD E3 ligase HRD1 was induced under Trypt-out conditions and promoted degradation of FASN (FIGS. 6J-6L). Together, these results supported a model in which Trp depletion selectively impairs translation of Trp-rich lipogenic enzymes, leading to lipid scarcity, ER stress, and activation of the UPR-ERAD axis, culminating in HRD1-mediated degradation of FASN).Example 8: Materials and Methods

[0154] KEY RESOURCE TABLE- 49 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086- 50 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086Animal Models

[0155] All procedures with animals were approved by the Institutional Animal Care and Use Committee of the University of Texas Southwestern Medical Center (approval number: 2017-101798) and followed the guidelines from National Institutes of Health (NIH). Mice were housed at 22°C with 30-70% humidity. To start diet experiments, the mice were fed with chow diet (inotiv: 2916) or special diets (see star methods) according to the experiment. All cages with mice were changed out every other week and health checks were performed by the UTSW veterinary team twice a day. The food and water were given as ad libitum. Male and female mice were acquired from Jackson lab. Six to ten-week-old male and female C57BL / 6J, homozygous obese spontaneous mutation ob / ob (Strain #:000632) obtained from Jackson Laboratories were used. For experiments with synthetic diet mice were for three, five, thirteen weeks with synthetic diet (www.inotiv.com) that lacks single amino acid and the control diet with all amino acids. For the diet-induced obese mice High Fat Diet (HFD with 60% of Kcal from fat, was used for 12 weeks.

[0156] Diets: For synthetic diet, mice were fed diets lacking a single amino acid or control diets (all obtained from Inovit) for 2 days-10 weeks to establish early and late effects of each intervention.

[0157] Diet composition- 51 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086

[0158] All diets were purchased from Inovit. Sucrose supplementation is provided by giving mice sucrose-containing water for the duration of the experiment. For Trp metabolite supplementation, intraperitoneal (IP) injections will be used primarily, and water supplementation will also be used at a later stage.

[0159] Cell culture: All cultured cells used were obtained from ATCC (www.atcc.org). The H2.35 hepatocytes (H2.35-CRL 1995) were cultured in DMEM with 5-10% fetal bovine serum (FBS), 100 U / rnL Penicillin-Streptomycin and 200 nM Dexamethasone. The 3T3 (3T3-L1 -CL-173) was keep as as H2.35 but without dexamethasone. For adipocyte differentiation, 3T3L1 cells were incubated with with 5mg / mL of insulin, 1 mM Dexamethasone and 0.5 mM isobutylmethylzanthine (IBMX). After two days, the media was changed for DMEM with 5 mg / mL insulin. During differentiation, the media was replaced every two days until day 10, maintaining just 5 mg / mL insulin. The experiments using tryptophan-depleted media, were conducted according to the manufacturer’s instructions (US Biologicals).Method details

[0160] Food intake and body weight measurements: Food intake and body weight were measured every week during the light cycle phase between 2 pm and 5 pm. For the measurements, the electronic balance device Bonvoisin Lab Scale (X002FL0N8H) was used.

[0161] Body composition: For the whole-body composition of the mice, an Echo MRI machine was used to acquire the lean mass and fat mass in grams and percentage of the body. The measurements were performed during the light cycle between 2 and 5 pm.

[0162] Blood glucose and GTT test: Contour next EZ blood glucose monitoring system (X002X2K05F) was used to measure blood glucose and for the GTT (glucose tolerance test). Blood glucose levels were measured after fa 4hour fast. GTT tests were conducted by giving intraperitoneal injection of glucose at 2.0 g I kg. Tail vein blood was collected at 0, 15, 30, 60, 90 and 120 minutes after glucose injection.- 52 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086

[0163] Hormone measurements: Bio-Plex Pro Mouse Diabetes 8-Plex Assay #171 F7001M for hormones analysis composed of 1 x 96-well kit with coupled magnetic beads, detection antibodies, standards, assay buffer, wash buffer, sample diluent, standard diluent, detection antibody diluent, streptavidin-PE, a filter plate, flat bottom plate, and sealing tape. The kit allowed for measurement of ghrelin, GIP, GLP-1, glucagon, insulin, leptin, PAI-1 and resistin. Serum of C57BL / 6J control diet and Trypt-out diet were collected.

[0164] Morphology and morphometries: White adipose tissue (gWAT), inguinal white adipose tissue (iWAT) and brown adipose tissue (BAT) were harvested and maintained for 48 hours in formalin 10% solution. After that, tissues were dehydrated in ethanol, embedded in paraffin and sectioned at with 5 mm. Hematoxylin and Eosin (HE) was used to visualize morphology. The HE sections were scanned using Nanozoomer S60 and analyzed using the AdipoQ plugin in Image J.

[0165] Metabolic cage: TSE pheno master environmental chambers were used to measure 02 consumption, CO2 production, RER, respiratory exchange rate and heat production by indirect calorimetry. Mice were previously acclimated for 5 days at the metabolic cages and then data was recorded light and dark phase of light cycle for 5 days or longer. Locomotor activity was recorded using the same equipment and data were collected at the same time.

[0166] Bomb calorimetry: Stools from 10 weeks old obese (ob / ob) male mice fed on control high fat diet and high fat Trypt-out diet for 5 weeks were harvested. The stool was submitted to the LITSW Mouse Metabolic Phenotyping Core for calorimetric analysis. Stool were dried in a centrifugal evaporator (Centrivap Concentrator, Labconco, Kansas City, MO) for 72 hours. After drying, the pellets were pulverized before analysis. A Parr (Moline, IL) 6200 Isoperibol Calorimeter equipped with a 6510 Parr Water Handling system and a semi-micro vessel was used to conduct the calorific tests. The gross heat of sample combustion (cal / g) is reported.

[0167] Cell proliferation: IncuCyte ZOOM Live-Cell Analysis System (Sartorius) was used to quantify proliferation for cell lines in 96-well plates which were followed 4-5 days. Growth was recorded every 2 h throughout the experiment with two parameters: cell count and confluence. The data was analyzed by scan from time 0.

[0168] RNA-seq: Liver, muscle, gWAT, iWAT and BAT from C57BL / 6J male 12 weeks old, fed on control diet and Trypt-out diet for 3 weeks were used. The tissue was frozen and proceeded for RNA-seq by Genewiz / Azenta. The data was analyzed using Trim Galore (vO.6.4) with the trimmed reads aligned to the human genome (GRCH38) or mouse genome (mm 10) using STAR (2.7.3a). Gene expression was quantified using feature Counts of the Subread (v1.6.3) package. Low-expressed genes (genes with the expression value of 0 in more than 30% of samples) were removed before any subsequent analysis. Gene expression- 53 - 301447048Attorney Docket No. UTSDP4183WO2- 1001375086was normalized using the Voom method from the R package limma (v 3.50.3). Differentially expressed genes were identified using the same package. Gene Set Enrichment Analysis (GSEA) for the DEGs was performed using R package clusterProfiler (v4.2.2). The analysis was performed by adopting Iog2 fold change, p-value 0.05 and Gene Enrichment Fisher’s exact test p-value 0.05.

[0169] Western Blot: For total protein extraction lysis buffer (RIPA buffer) was used containing protease and phosphatase inhibitors. SDS-polyacrylamide gel electrophoresis to separated proteins on 4-12% gradient gels and transferred to nitrocellulose membrane to blot with the specific antibodies (Key resources table). Western blots were done by chemiluminescence kit (Thermos Fisher-PI34076). The images were acquired using BioRad ChemiDocimager system.

[0170] Puromycylation: Puromycin was added at 20 pg / mL to the cells 2 hours before harvesting for protein extraction. After two hours of puromycin incubation, cells were in RIPA buffer for western blotting with anti-puromycin antibody (Key resources table).

[0171] LC-MS / MS: Trp metabolites in tissue (BAT, gWAT, iWAT and liver) were analyzed by LC-MS / MS performed by the LITSW Preclinical Pharmacology Core. The tissue samples were extracted, weighed and homogenized in a 3-fold volume of PBS using BeadBug microtube homogenizer prefilled tubes with 3.0mm Zirconium beads (Sigma Cat #Z763802), run for 2 minutes at 2800 rpm. 50 mL of each tissue sample were collected and crashed with 200 mL methanol, and incubated at RT for 10 minutes and spun in a tabletop, chilled centrifuge for 5 minutes at 14K rpms. Supernatant was transferred to an eppendorf tube and dried down using a SpeedVac. The dried sample was resuspended in 0.1 mL ddH2O + 25 ng / mL tolbutamide IS + 10 ng / mL d5 Trp IS + 100 ng / mL d5 IAA IS. Standards were made by combining equal amounts of tissues (in final resuspension solution) as a background matrix. The standard mix was diluted with resuspension solution 1:1000 for Kynurenine, KA, CA, 3HAA, 5HTP, and XA standards, 1:5000 for Tryptophan, NFK, Melatonin, 5HIAA, and Serotonin standards, 1:5000 for AA and I3CA standards, and 1:5000 for NFAA, I3LA, I3PA and Tryptamine standards.100uL of diluted standard mix were spiked with 1uL of the appropriate standard at varying concentrations. Samples were transferred to a low volume 96-well HPLC plate and analyzed by LCMS.

[0172] Metabolomics: For the extraction of metabolites, -20-25 mg of frozen tissue was collected, to which 300 uL of ice-cold methanol / water 80:20 (vol / vol) was added then homogenized using the blue pestle / manual homogenizer (Sigma Z359947). Next, the homogenized sample was centrifuged at -20,160 xg for 15 min in a refrigerated centrifuge, the metabolite containing supernatant transferred into a new tube with a volume equivalent to- 54 - 301447048Attorney Docket No. UTSDP4183WO2- 100137508610 mg of protein, then resuspended in 100 mL acetonitrile / water 80:20 (vol / vol) for a final concentration of [0.1mg / mL] of protein (of the supernatant). The metabolites in the samples were then measured by LC-MS-MS at the Metabolomics core at Children’s Research Institute at UTSW.

[0173] Quantification and analysis: All analyses were performed using two-tailed unpaired students T-tests or ANOVA with p < 0.05 designated as significant. All values are reported as mean ± SD in each figure.REFERENCES

[0174] 1. Lafita-Navarro, M.C., Hao, Y.H., Jiang, C., Jang, S., Chang, T.C., Brown, I.N., Venkateswaran, N., Maurais, E., Stachera, W., Zhang, Y., et al. (2023). ZNF692 organizes a hub specialized in 40S ribosomal subunit maturation enhancing translation in rapidly proliferating cells. Cell Rep 42, 113280. 10.1016 / j.celrep.2023.113280.

[0175] 2. Lafita-Navarro, M.C., Kim, M., Borenstein-Auerbach, N., Venkateswaran, N., Hao, Y.H., Ray, R., Brabletz, T., Scaglioni, P.P., Shay, J.W., and Conacci-Sorrell, M. (2018). The aryl hydrocarbon receptor regulates nucleolar activity and protein synthesis in MYC-expressing cells. Genes Dev 32, 1303-1308. 10.1101 / gad.313007.118.

[0176] 3. Venkateswaran, N., Garcia, R., Lafita-Navarro, M.C., Hao, Y.H., Perez-Castro, L., Nogueira, P.A.S., Solmonson, A., Mender, I., Kilgore, J. A., Fang, S., et al. (2024). Tryptophan fuels MYC-dependent liver tumorigenesis through indole 3-pyruvate synthesis. Nat Commun 15, 4266. 10.1038 / s41467-024-47868-3.

[0177] 4. Zeitler, L., Fiore, A., Meyer, C., Russier, M., Zanella, G., Suppmann, S., Gargaro, M., Sidhu, S.S., Seshagiri, S., Ohnmacht, C., et al. (2021). Anti-ferroptotic mechanism of I L4i1 -mediated amino acid metabolism. Elife 10. 10.7554 / eLife.64806.- 55 - 301447048

Claims

Attorney Docket No. UTSDP4183WO2- 1001375086CLAIMSWhat is claimed is:

1. A dietary product comprising at least 3 essential amino acids selected from a group consisting of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, and valine; wherein the dietary product is substantially devoid of tryptophan.

2. The dietary product of claim 1 , wherein the dietary product is for treating or preventing obesity or a metabolic disease in a subject in need thereof.

3. A method of treating or preventing obesity or a metabolic disease in a subject in need thereof, the method comprising administering a controlled diet to the subject, wherein the controlled diet is substantially devoid of tryptophan.

4. The dietary product of claim 1 or claim 2, wherein the dietary product comprises less than 0.5 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.05 mg, or 0.001 mg of tryptophan per 100 grams of the dietary product.

5. The dietary product of claim 1 or claim 2, wherein the composition comprises no tryptophan.

6. The dietary product of any one of claims 1 , 2, or 4, wherein the dietary product is part of a controlled diet for a subject in need thereof; wherein the controlled diet comprises less than 0.5 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.05 mg, or 0.001 mg of tryptophan per 100 grams of food intake.

7. The dietary product of any one of claims 1 , 2, or 4, wherein the product comprises at least 4, at least 5, at least 6, at least 7, or 8 of the essential amino acids (excluding tryptophan).

8. The dietary product of any one of claims 1, 2, 6, or 7, wherein each of the at least 4, at least 5, at least 6, at least 7, or 8 of the essential amino acids are in an amount of 0.01 mg to 10 mg per 100 grams of the dietary product.

9. The dietary product of any one of 1, 2, or 4-8, further comprising one or more non-essential amino acids selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, and tyrosine.

10. The dietary product of claim 9, wherein the dietary product comprises at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or all of the non-essential amino acids.- 56 - 301447048Attorney Docket No. UTSDP4183WO2- 100137508611. The dietary product of any one of claims 1 , 2, or 4-10, further comprising one or more macronutrient and / or one or more micronutrient source, or any combination thereof.

12. The dietary product of claim 11, wherein the micronutrient comprises one or more vitamins, one or more macro minerals, or one or more trace minerals.

13. The dietary product of any one of claims 1, 2, or 4-12, wherein the dietary product comprises about 7-10 g of leucine, 4-6 g of isoleucine, 4-5 g of valine, 6-8 g of lysine, 1-3 g of methionine, 2-3 g of phenylalanine, 5-7 g of threonine, 1-2 g of histidine, 4-5 g of alanine, 2-3 g of arginine, 9-13 g of aspartic acid, 14-16 g of glutamic acid, 1-2 g of glycine, 4-5 g of proline, 3-5 g of serine, or 2-3 g of tyrosine, or any combination thereof, per 100 g of protein.

14. The dietary product of any one of claims 1, 2, or 4-12, wherein the dietary product comprises about 7-10 g of leucine, 4-6 g of isoleucine, 4-5 g of valine, 6-8 g of lysine, 1-3 g of methionine, 2-3 g of phenylalanine, 5-7 g of threonine, 1-2 g of histidine, 3-5 g of alanine, 2-3 g of arginine, 9-13 g of aspartic acid, 14-16 g of glutamic acid, 1-2 g of glycine, 4-5 g of proline, 3-5 g of serine, and 2-3 g of tyrosine per 100 g of protein.

15. The dietary product of any one of claims 1, 2, 4-12, wherein the dietary product comprises, per kilogram of the dietary product, about 9-13 g of leucine, 6-10 g of isoleucine, 6-10 g of valine, 16-20 g of lysine, 6-10 g of methionine, 6-10 g of phenylalanine, 6-10 g of threonine, 3-6 g of histidine, 2-6 g of alanine, 10-14 g of arginine, 2-6 g of aspartic acid, 38-42 g of glutamic acid, 21-25 g of glycine, 2-6 g of proline, 2-6 g of serine, or 3-7 g of tyrosine, or any combination thereof.

16. The dietary product of any one of claims 1, 2, or 4-15, wherein the dietary product is in the form of a powder, a gel, a solution, a suspension, a paste, a solid, a pellet, a liquid, a liquid concentrate, a powder which may be reconstituted, a shake, a concentrate, a pill, a bar, a tablet, a capsule, injectable solution, or a ready-to-use product.

17. The dietary product of any one of claims 1, 2, or 4-16, further comprising a serotonin supplement.

18. The dietary product of any one of claims 1, 2, or 4-17, further comprising one or more of 5-hydroxytryptophan (5-HTP), St. John’s Wort, S-adenosylmethionine (SAMe), vitamin B6, L-methylfolate, magnesium, omega-3 fatty acids, or vitamin D.

19. The method of claim 3, wherein the controlled diet comprises less than 0.5 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.05 mg, or 0.001 mg of tryptophan per 100 grams of food intake.- 57 - 301447048Attorney Docket No. UTSDP4183WO2- 100137508620. The method of any one of claims 3 or 19, wherein the controlled diet comprises no tryptophan.

21. The method of any one of claims 3, 19, or 20, wherein the controlled diet changes the overall daily calorie intake by the subject by less than 1%-25%.

22. The method of any one of claims 3, or 19-21, wherein the controlled diet is for less than 6 months, 5 months, 4 months, 3 months, 2 months, 1 month, 3 weeks, or 2 weeks.

23. The method of any one of claims 3, or 19-22, wherein the method comprises administering to the subject a dietary product substantially devoid of tryptophan.

24. The method of 22, wherein the method comprises administering to the subject a dietary product of any one of claims 1 , 2, or 4-18.

25. The method of any one of claims 23 or 24, wherein the dietary product forms at least, or about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% of the subject’s diet.

26. The method of any one of claims 23-25, wherein the dietary product comprises at least 4, at least 5, at least 6, at least 7, or all the essential amino acids.

27. The method of any one of claims 23-26, wherein the dietary product comprises each of the at least 4, at least 5, at least 6, at least 7, or all of the essential amino acids in an amount of 0.01 mg to 10 mg per 100 grams of the dietary product.

28. The method of any one of claims 23-27, wherein the dietary product further comprising one or more non-essential amino acids selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, and tyrosine.

29. The method of claim 28, wherein the dietary product further comprises at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or all of the non-essential amino acids.

30. The method of any one of claims 27-29, wherein the dietary product further comprises one or more macronutrient and / or one or more micronutrient source, or any combination thereof.

31. The method of claim 30, wherein the dietary product comprises one or more vitamins, one or more macro minerals, or one or more trace minerals.- 58 - 301447048Attorney Docket No. UTSDP4183WO2- 100137508632. The method of any one of claims 30 or 31 , wherein the dietary product comprises one or more lipids, and / or one or more carbohydrates.

33. The method of any one of claims 3 or 19-32, further comprising administering to the subject a serotonin supplement.

34. The method of any one of claims 3 or 19-33, further comprising administering to the subject one or more of 5-hydroxytryptophan (5-HTP), St. John’s Wort, S-adenosylmethionine (SAMe), vitamin B6, L-methylfolate, magnesium, omega-3 fatty acids, or vitamin D.

35. The method of any one of claims 3, or 19-32, wherein the subject is a mammal.

36. The method of claim 35, wherein the subject is a human.

37. The method of any one of claims 3, or 19-36, wherein the obesity or the metabolic disease is diabetes (type 1, type 2 [diet-treated, sulfonylurea-treated, long-term insulin-treated], gestational, autoimmune, obese, borderline type), obesity, metabolic syndrome, inflammatory bowel syndrome, diabesity, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia (high LDL, low HDL), postprandial hyperlipemia, insulin resistance, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), hyperglycemia, nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fatty liver disease (from obesity or diabetes), hypertension, or hypertensive nephrosclerosis, or any combination thereof.

38. The method of any one of claims 3, or 19-37, wherein the method further comprises administering to the subject one or more additional treatments for obesity, and / or for the metabolic disease.

39. The method of claim 38, wherein the additional treatment for obesity and / or metabolic disease comprises exercise, weight loss medications (e.g., orlistat, GLP-1 receptor agonists like semaglutide, liraglutide), bariatric surgery (e.g., gastric bypass, sleeve gastrectomy), behavioral therapy, insulin sensitizers (e.g., metformin, thiazolidinediones), lipid-lowering agents (e.g., statins, fibrates), antihypertensives (e.g., ACE inhibitors, ARBs), appetite suppressants, or lifestyle interventions, or any combination thereof.

40. A dietary regimen kit, the regimen kit comprising meals for a controlled diet, wherein the controlled diet is substantially devoid of tryptophan.

41. The dietary regimen kit of claim 40, comprising the dietary composition of any one of claims 1-3 or claims 4-17.- 59 - 301447048Attorney Docket No. UTSDP4183WO2- 100137508642. The dietary regimen kit of claim 40, wherein the meals comprise pre-packaged meals, each comprising less than 0.5 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.05 mg, or 0.001 mg of tryptophan per 100 grams of food.

43. The dietary regimen kit of claim 40 or claim 42, wherein the dietary regimen kit further comprises instructions for using the kit.

44. The dietary regimen kit of claim 40, wherein the dietary regimen kit if for use for treating or preventing obesity, and / or a metabolic disease.- 60 - 301447048

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