Weight management composition

Abstract

The invention provides a method of promoting weight management in a mammal comprising administering to the mammal a composition comprising at least one weight loss agent and at least one mitochondrial enhancer. The weight loss agent can be selected from the group consisting of psyllium, guar gum, capsaicin, chitosan, caffeine, gamboge, mume, capsaicin, yohimbine, butterfly pea, glucomannan, African mango, guarana, pyruvate, carnitine, beta-glucan, fucoxanthin, raspberry ketone, white kidney bean, kola nut, chromium, ginseng, psyllium, St. John's wort, dandelion, hydroxycitric acid, conjugated linoleic acid, green tea, black tea, coffee bean extract, forskolin, and bitter orange. The mitochondrial enhancer can be selected from the group consisting of beetroot extract, nitrate, idebenone, nicotinamide riboside, elamipretide, vitamin C, vitamin D, vitamin E, thiamine, riboflavin, magnesium, calcium, phosphate, phospholipid, creatine, pyruvate, coenzyme Q10, NADH, niacin, L-carnitine, dichloroacetate, curcumin, schisandrin, and resveratrol. Compositions for weight management are also provided.

Description

Technical Field

[0001] The present invention generally relates to compositions and methods for improving individual health, and more specifically to compositions and methods for promoting individual weight management. Background Technology

[0002] The prevalence of overweight and obesity has become one of the most significant health problems facing the world. In the past 30 years, the incidence of obesity has almost tripled, with approximately 40% of adults aged 18 and over being overweight and about 13% obese globally. Obesity is well-known to be linked to the development of many other diseases, such as fatty liver disease, cardiovascular disease, type 2 diabetes, hypertension, dyslipidemia, gallbladder disease, osteoarthritis, sleep apnea, asthma, chronic kidney disease, and depression. Obesity is caused by an imbalance between an individual's total energy expenditure and energy intake. Therefore, these obesity-related comorbidities can be prevented or treated by losing weight.

[0003] One of the most effective strategies available for weight loss is participating in structured programs of physical exercise, such as endurance or resistance training. Studies conducted over the past few decades have repeatedly shown that exercise or physical activity increases energy expenditure, thereby promoting weight loss and improving health; however, the majority of the population in most countries does not reach the recommended levels. The main reasons individuals do not participate in exercise include inconvenience, cost, time-consuming nature, difficulty in execution, boredom, or unpleasantness.

[0004] Eating healthy, balanced foods without overeating is a way to reduce energy intake to promote fat loss and maintain good health. However, similar to exercise, there are many obstacles to eating healthy foods, such as limited access to food, the higher cost and time required to prepare food, and the fact that many healthy foods or meals are less palatable than unhealthy alternatives. Furthermore, even with weight loss achieved through diet and exercise, the amount of fat reduction is often insufficient to meet the full amount of weight loss an individual needs to maintain optimal health.

[0005] Therefore, there is a need to provide improved weight management compositions and methods for improving individual health. Summary of the Invention

[0006] Weight management compositions have now been developed and have been shown to promote weight loss in individuals.

[0007] Therefore, in a first aspect of the invention, a weight management composition is provided, the composition comprising a weight loss agent and a mitochondrial enhancer.

[0008] In one embodiment, a weight management composition comprising a weight loss agent and a mitochondrial enhancer is provided, wherein the weight loss agent comprises green tea extract, green coffee bean extract, and saliva extract, and the mitochondrial enhancer comprises beetroot extract, coenzyme Q10, alpha-lipoic acid, and vitamin E.

[0009] In another aspect of the invention, a method for promoting weight management in mammals is provided, the method comprising the step of administering a weight management composition comprising a weight loss agent and a mitochondrial enhancer to the mammal.

[0010] In another aspect, a method is provided for treating or improving at least one of the following in mammals: weight, body fat, mitochondrial capacity, fatty liver disease, dyslipidemia, oxidative stress level, brown adipose tissue activity, and systemic inflammation level, said method comprising administering to said mammal a composition comprising a weight-loss agent and a mitochondrial enhancer.

[0011] These and other aspects of the invention will become apparent from the following detailed description with reference to the accompanying drawings. Attached Figure Description

[0012] Figure 1 The diagram illustrates the weight of mice fed with the weight management composition or control food and assigned to sedentary or exercise-trained conditions for 30 days.

[0013] Figure 2 Illustration: A) Relative fat mass and B) relative muscle mass of mice fed with weight management composition or control food and given to mice in sedentary or exercise training conditions for 30 days.

[0014] Figure 3 The diagram illustrates the relative weights of the following tissues in mice fed with the weight management composition or control diet and assigned to sedentary or exercise-trained conditions for 30 days: A) abdominal fat pad, B) liver, and C) tibialis anterior muscle (TA; sum of both recorded).

[0015] Figure 4 The diagram illustrates the relative weights of the following tissues in mice fed a weight management composition or control diet and assigned to sedentary or exercise-trained conditions for 30 days: A) quadriceps femoris (Quad; sum of both recorded), B) heart, C) pancreas, and D) interscapular brown adipose tissue (BAT).

[0016] Figure 5 The diagram illustrates the food intake of mice at the endpoint timeline when they were fed a weight management composition or a control diet and were assigned to either a sedentary or exercise training condition for 30 days.

[0017] Figure 6The diagram illustrates A) maximum motor ability and B) rotarod performance in mice fed a weight management composition or control diet and given to sedentary or exercise-trained conditions for 30 days.

[0018] Figure 7 The diagram illustrates the various formulations of the weight management composition or control food given to mice under sedentary or exercise training conditions for 30 days.

[0019] Figure 8 The diagram illustrates the relative fat mass and muscle mass (A) of mice fed with weight management compositions or control foods and administered to mice under sedentary or exercise-trained conditions for 30 days.

[0020] Figure 9 The diagram illustrates the various formulations of weight management compositions or control foods administered to mice under sedentary or exercise-trained conditions for 30 days, including A) abdominal fat pad, B) liver, and C) TA muscle (both recorded).

[0021] Figure 10 The diagram illustrates the relative weights of the following tissues in mice fed with weight management compositions or control foods for 30 days under sedentary or exercise-trained conditions: A) Quad (sum of both records), B) Heart, C) Pancreas, and D) Interscapular BAT.

[0022] Figure 11 The diagram illustrates the various formulations of weight management compositions or control foods fed to mice under sedentary or exercise training conditions for 30 days, and their maximum exercise capacity in the following categories: A) baseline and B) endpoint.

[0023] Figure 12 The diagram illustrates various formulations of weight management compositions or control foods administered to skeletal muscle mice under sedentary or exercise-trained conditions for 30 days: A) uncoupled mitochondrial respiration of Complex 1 in State 2, B) support for submaximal oxygen consumption in State 3 by Complexes I and II, and C) the ratio of COXIV enzyme activity to citrate synthase activity (COX / CS).

[0024] Figure 13 The diagram illustrates the expression of white adipose tissue mRNA in mice fed various formulations of weight management compositions or control foods and administered to mice under sedentary or exercise-trained conditions for 30 days, as biomarkers of fat oxidation and mitochondrial capacity: A) PGC1α, B) COX2, C) PPARα, D) HSL, and E) SCHAD.

[0025] Figure 14The diagram illustrates various formulations of weight management compositions or control foods and the expression of white adipose tissue mRNA as biomarkers of browning in white adipose tissue in mice given to sedentary or exercise-trained conditions for 30 days: A) uncoupling protein 3 (UCP3), B) PRDM16, C) CIDEA, and D) ADIPOQ.

[0026] Figure 15 The diagram illustrates the skeletal muscle abundance of the following animals in mice fed various formulations of weight management compositions or control foods and administered under sedentary or exercise-training conditions for 30 days: A) 4-HNE and B) p62.

[0027] Figure 16 The diagram illustrates mice fed various weight management compositions or control diets and given to mice under sedentary or exercise-trained conditions for 30 days: A) serum ApoB concentration, B) serum ApoA1 concentration, C) serum ApoB / ApoA1 ratio, D) serum PCSK9 concentration, and E) gene expression of biomarkers for hepatic lipid synthesis and cholesterol uptake.

[0028] Figure 17 The diagram illustrates mice fed various weight management compositions or control diets and given to mice under sedentary or exercise-training conditions for 30 days: A) liver triglycerides, B) liver steatosis score, and C) serum ALT activity.

[0029] Figure 18 The diagram illustrates the expression of gene markers for hepatic lipid synthesis and endoplasmic reticulum stress in mice fed various weight management compositions or control diets and given to mice under sedentary or exercise-trained conditions for 30 days: A) expression of gene markers for hepatic lipid synthesis and B) expression of gene markers for hepatic endoplasmic reticulum stress.

[0030] Figure 19 The diagram illustrates the expression of gene markers for programmed cell death in the liver, and gene markers for liver inflammation and fibrosis, in mice fed various weight management compositions or control diets and given to mice under sedentary or exercise-trained conditions for 30 days: A) and B) respectively.

[0031] Figure 20 The diagram illustrates the expression of systemic inflammatory biomarkers in white adipose tissue mRNA in mice fed various formulations of weight management compositions or control foods and administered under sedentary or exercise-trained conditions for 30 days: A) IL1β and B) TNFα.

[0032] Figure 21 The diagram illustrates the lipid oxidation rates in mice fed various formulations of weight management compositions or control foods and administered under sedentary or exercise-trained conditions for 30 days; A) day-1 and B) days 1-3, and activity levels on C) day-1 and D) days 1-3. Detailed Implementation

[0033] We provide a weight management composition containing a weight loss agent and a mitochondrial enhancer, which can be used to treat or improve health conditions in mammals, such as weight management, mitochondrial capacity, fatty liver disease, dyslipidemia, oxidative stress levels, brown adipose tissue (BAT) activity, and systemic inflammation levels.

[0034] The term "weight management" is used in this article to refer to achieving or maintaining a weight within a healthy normal range. One of the most widely used metrics for measuring weight is the "Body Mass Index" or BMI. A BMI range of approximately 18.5 to 24.9 is considered within the healthy normal range, meaning a weight that contributes to an individual's health, fitness, well-being, and physical appearance. Overweight and obesity are defined as abnormal or excessive accumulation of fat that may lead to impaired health. Individuals with a BMI between approximately 25 and 29.9 are generally considered overweight, while individuals with a BMI of 30 or higher are generally considered obese. Weight management can also refer to maintaining body fat levels within a healthy range, such as the percentage of body fat that contributes to an individual's health, fitness, well-being, and physical appearance. Examples of a healthy body fat range can range from baseline body fat levels (the amount considered essential for physical and mental health) to approximately 20% above baseline body fat levels. According to the American Council on Exercise, the amount of fat considered essential for men is approximately 2% to 5% of body fat, while for women it is approximately 10% to 13%.

[0035] The weight management composition comprises at least one weight-loss agent. The weight-loss agent can be any suitable agent with characteristics that promote weight loss in mammals, such as a reduction in body weight of at least about 0.5%, preferably about 1% or more, compared to pre-treatment weight with the composition of the present invention, for example, an individual weight reduction of 5%, 10%, 30%, 50%, 70%, or more, or a reduction in the rate of weight gain of at least about 1% or more compared to pre-treatment weight, and preferably a reduction of about 5% or more, for example, a reduction in the rate of weight gain of 10%, 30%, 50%, 70%, 90%, or higher. Suitable weight-loss agents can promote weight loss through any one or more of several mechanisms, including but not limited to: reducing food intake or promoting satiety, reducing lipid absorption, increasing energy expenditure, reducing preadipocyte differentiation and proliferation, reducing lipogenesis or lipolysis, or increasing lipid oxidation. Examples of weight loss agents include, but are not limited to: chitosan, psyllium, guar gum, capsaicin, caffeine, gamboge, red pine, capsaicin, yohimbine, hoodia, glucomannan, African mango, guarana, pyruvate, carnitine, beta-glucan, fucoxanthin, raspberry ketone, white kidney bean, kola nut, chromium, ginseng, psyllium, St. John's wort, dandelion, hydroxycitric acid, conjugated linoleic acid, green tea extract, black tea extract, green coffee bean extract, edamame, bitter orange, and mixtures thereof.

[0036] In one embodiment, the weight loss agent comprises a mixture of green tea extract, green coffee bean extract, and trichosamine.

[0037] In another embodiment, the weight-loss agent comprises a mixture of green tea extract, black tea extract, green coffee bean extract, conjugated linoleic acid, and trichosin.

[0038] The green tea extract used in the compositions of this invention can be selected from any suitable green tea leaves or green tea source, such as sencha, Fukamushi Sencha, Gyokurocha, Kabusecha, matcha, tencha, genmaicha, matcha, shincha, hojicha, Ichibancha (green tea), Nibancha (green tea), and Sanbancha (green tea), which are derived from camellia leaves. Green tea is high in polyphenols such as catechins. Examples of such catechins include epigallocatechin gallate, catechinic acid, catechin gallate, epicatechin, gallocatechin, epirheic catechin, and epicatechin. Preferably, on a dry weight basis, the green tea extract used in the composition contains about 80% or more catechins, of which about 50% or more are epicatechin gallate catechins. The green tea extract used in the compositions of the present invention may be caffeinated or substantially caffeine-free, for example, having less than 1% caffeine by dry weight. In one embodiment, the green tea extract comprises about 0.1% to 90% of the dry weight of the weight management composition, for example, about 5% to 50% or about 10% to 30% of the dry weight of the composition. In another embodiment, the weight management composition comprises a daily dose of about 10 mg to 5 g of green tea extract, preferably about 50 to 1000 mg.

[0039] The green coffee bean extract used in the compositions of the present invention can be selected from any suitable source of green coffee beans, such as Coffea Arabica or Coffea canephora. Green coffee beans contain various types of chlorogenic acids, such as 3-caffeoylquinic acid, 4-caffeoylquinic acid, and 5-caffeoylquinic acid. Preferably, the green coffee bean extract used in the compositions of the present invention contains about 30% or more of chlorogenic acid by dry weight. The green coffee bean extract used in the compositions of the present invention can be caffeinated or substantially caffeine-free, for example, having less than 1% caffeine by dry weight. Preferably, the green coffee bean extract contains at least 35% chlorogenic acid and at least 35% caffeine by dry weight. In one embodiment, the green coffee bean extract constitutes about 0.1-80% of the dry weight of the weight management composition, for example, about 5-50% or about 10-30% of the dry weight of the composition. In another embodiment, the weight management composition comprises a daily dose of about 10 mg to 5 g of green coffee bean extract, preferably about 50-1000 mg.

[0040] The trichosanthesin used in the compositions of the present invention can be obtained from any suitable source. Trichosanthesin can be extracted from or synthesized from the *Cotinus coggygria* plant. Preferably, the trichosanthesin extract is derived from the *Cotinus coggygria* plant and is standardized to contain about 40% trichosanthesin. In one embodiment, trichosanthesin constitutes about 0.05 to 50% of the dry weight of the weight management composition, for example, about 0.1 to 30% or about 0.5 to 10% of the dry weight of the composition. In another embodiment, the weight management composition contains a daily dose of about 1 mg to 200 mg of trichosanthesin, preferably about 15 mg to 100 mg.

[0041] The black tea extract used in the compositions of the present invention can be obtained from any suitable black tea leaves or tea source, including unmixed black tea sources such as Kungu, Assam, Darjeeling, Nilgiri, or Ceylon, or blended black teas such as Earl Grey, English Breakfast Tea, English Afternoon Tea, Irish Breakfast Tea, or Masala Chai, all derived from the leaves of the Camilla sinensis. Black tea is rich in polyphenols such as theaflavins, thearubigins, and catechins. Examples of theaflavins include theaflavins, theaflavins-3-gallate, theaflavins-3'-gallate, and theaflavins-3,3'-gallate. Preferably, the black tea extract used in the compositions of the present invention contains 10% or more polyphenols by dry weight. The black tea extract used in the compositions of the present invention can be caffeinated or substantially decaffeinated, for example, having less than 1% caffeine by dry weight. Preferably, the black tea extract contains at least about 30% polyphenols by dry weight. In one embodiment, the black tea extract comprises about 0.1% to 80% of the dry weight of the weight management composition, for example, about 5% to 50% or about 10% to 30% of the dry weight of the composition. In another embodiment, the weight management composition comprises a daily dose of about 10 mg to 5 g of black tea extract, preferably about 50 to 750 mg.

[0042] The conjugated linoleic acid used in this application may be derived from any suitable source, such as safflower oil, sunflower seed oil, or grass-fed beef. As used herein, the term "conjugated linoleic acid" refers to any of at least 28 known geometric or positional isomers of linoleic acid, wherein the two double bonds of the molecule are conjugated, for example in the cis-9:trans-11 or trans-10:cis-12 form. The composition may comprise a single isomer, isomers, a mixture of natural isomers, synthetic isomers, or pharmaceutically acceptable salts, esters, monoglycerides, diglycerides, triglycerides, their metabolic precursors, or any combination thereof. Preferably, the conjugated linoleic acid comprises about a 50:50 mixture of its cis-9:trans-11 and trans-10:cis-12 isomers. In one embodiment, the conjugated linoleic acid source constitutes about 1% to 80% of the dry weight of the weight management composition, for example, about 20% to 70% or about 30% to 50% of the dry weight of the composition. In another embodiment, the weight management composition comprises a daily dose of about 10 mg to 10 g of conjugated linoleic acid, preferably about 500 mg to 3 g.

[0043] The weight management composition contains at least one mitochondrial enhancer. The mitochondrial enhancer may be selected from any suitable agent that enhances the capabilities of mitochondria in mammals, for example by increasing mitochondrial abundance, increasing mitochondrial ATP production capacity, protecting mitochondria from excessive oxidative stress, and promoting the maintenance of mitochondrial components, ion gradients, and ultrastructure, for example by increasing mitophagy events or increasing mitochondrial fission and fusion events.

[0044] In one embodiment, the mitochondrial enhancer is selected from at least one of the following: beet root extract, nitrate, idebenone, nicotinamide riboside, ilatropin, vitamin C, vitamin D, vitamin E, thiamine, riboflavin, magnesium, calcium, phosphate, membrane phospholipids, creatine, pyruvate, coenzyme Q10, NADH, niacin, L-carnitine, dichloroacetate, curcumin, schisandrin, resveratrol, and mixtures thereof.

[0045] In one embodiment, the mitochondrial enhancer comprises a mixture of beetroot extract, coenzyme Q10, alpha-lipoic acid, and vitamin E.

[0046] In another embodiment, the mitochondrial enhancer comprises a mixture of beetroot extract, coenzyme Q10, alpha-lipoic acid, creatine, and vitamin E.

[0047] The beetroot extract used in the compositions of the present invention can be selected from any suitable beetroot source, including red beets such as Detroit Dark Red, Red Ace, Early WonderTall Top, Buffalo Blood, Floro, Ruby Queen, Chioggia, Serendra, or Gladiator; yellow or golden beets such as Yellow Detroit Beet, Golden Beet, Touchstone Beet, or Coarse Beet; or white beets such as Avalanche Beet, Baby White Beet, Blank Beet, or Cedar Beet. Preferably, the beetroot extract is substantially derived from the main root portion of the beetroot. In one embodiment, the beetroot extract used in the compositions of the present invention contains at least about 1.5% nitrate by dry weight. In another embodiment, the beetroot extract comprises about 0.1% to 90% of the dry weight of the weight management composition, for example, about 1% to 50% or about 5% to 25% of the dry weight of the composition. In another embodiment, the weight management composition comprises a daily dose of about 10 mg to 50 g of beetroot extract, preferably about 50 to 5000 mg.

[0048] Coenzyme Q10, also known as ubiquinone, ubiquitinone, coenzyme Q, CoQ10, CoQ, or Q10, can be used in this composition in any of three redox states: fully oxidized (ubiquinone), half-oxidized (half-quinone or ubiquitin), and fully reduced (panthenol), as well as the oxidized mitochondrial-targeted form of the enzyme (e.g., mitoxantrone methanesulfonate (MitoQ10)). As those skilled in the art will understand, coenzyme Q10 can be formulated in a variety of ways to improve its bioavailability or efficacy. Examples of such formulations used in the compositions of the present invention include, but are not limited to: colloidal, solid dispersion-based, oily dispersion-based, micellar-based, nanoliposome-based, nanostructure-based lipid carrier-based, nanocrystal-based, nanoparticle-based, self-nanoemulsifying, chelated, and cyclodextrin-based complexed ascorbic acid. In one embodiment, coenzyme Q10 constitutes about 0.1% to 80% of the dry weight of the weight management composition, for example, about 1% to 50% or about 5% to 20% of the dry weight of the composition. In another embodiment, the weight management composition comprises a daily dose of about 10 mg to 1 g of coenzyme Q10, preferably about 50 to 900 mg.

[0049] The alpha-lipoic acid suitable for the compositions of the present invention may include, but is not limited to, alpha-lipoic acid or its reduced form, dihydrolipoic acid, wherein the R- and S-enantiomers may be present alone, in racemic form, or in any other mixture thereof. The R enantiomer is naturally or synthetically produced, while the S enantiomer is synthetically produced only, not naturally produced. Furthermore, any pharmaceutically acceptable salt or derivative thereof is suitable for the compositions of the present invention. Preferably, alpha-lipoic acid is present in a racemic form. In one embodiment, alpha-lipoic acid constitutes about 0.1% to 90% of the dry weight of the weight management composition, for example, about 5% to 50% or about 10% to 30% of the dry weight of the composition. In another embodiment, the weight management composition comprises a daily dose of about 10 mg to 10 g of alpha-lipoic acid, preferably about 50 mg to 900 mg.

[0050] Creatine used in the compositions of the present invention can be in any suitable form, such as creatine monohydrate, anhydrous creatine, creatine citrate, creatine ascorbate, creatine ethyl ester, creatine nitrate, creatine magnesium chelate, creatine salt, creatine malate, creatine pyruvate, creatine phosphate, creatine citrate malate, creatine tartrate, creatine HMB (β-hydroxyβ-methylbutyric acid), effervescent creatine, titrated creatine, buffered creatine, micronized creatine, and any combination thereof. Preferably, creatine is creatine monohydrate. In one embodiment, creatine constitutes about 1% to 90% of the dry weight of the weight management composition, for example, about 20% to 70% or about 30% to 50% of the dry weight of the composition. In another embodiment, the weight management composition comprises a daily dose of about 0.1 to 10 g of creatine, preferably about 0.5 to 5 g.

[0051] Vitamin E used in the compositions of the present invention may be present in any one or more of its isomers, including α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol, and their stereoisomers. Vitamin E may also be used in similar forms, comprising, for example, vitamin E esters (e.g., in the form of acetate, succinate, or palmitate) or other forms of vitamin E that have been modified to improve stability or bioavailability. Preferably, the form of vitamin E used in the composition is α-tocopherol, comprising a biologically functional stereoisomer of α-tocopherol, such as the naturally occurring RRR configuration or the synthetically produced 2R stereoisomers (RSR, RRS, and RSS). In the most preferred embodiment, the vitamin E used is D (also known as RRR) α-tocopherol acetate. In one embodiment, vitamin E constitutes about 0.1% to 80% of the dry weight of the weight management composition, for example, about 1% to 50% or about 3% to 15% of the dry weight of the composition. In another embodiment, the weight management composition contains a daily dose of about 10 mg to 1 g of vitamin E, preferably about 50 to 900 mg.

[0052] In one embodiment, the weight management composition comprises a mixture as a weight loss agent and a mixture as a mitochondrial enhancer. The mixture as the weight loss agent comprises 50-1000 mg of green tea extract, 50-1000 mg of green coffee bean extract, and 15-100 mg of saliva extract at a daily dose. The mixture as the mitochondrial enhancer comprises 50-5000 mg of beetroot extract, 50-900 mg of coenzyme Q10, 50-900 mg of alpha-lipoic acid, and 50-900 mg of vitamin E at a daily dose.

[0053] In another embodiment, the weight management composition comprises a mixture as a weight loss agent and a mixture as a mitochondrial enhancer. The mixture as a weight loss agent comprises 50-500 mg of green tea extract, 50-500 mg of black tea extract, 50-500 mg of green coffee bean extract, 500 mg-3 g of conjugated linoleic acid, and 15 mg-50 mg of trichomoniasis extract at a daily dose. The mixture as a mitochondrial enhancer comprises 100-1000 mg of beetroot extract, 50-200 mg of coenzyme Q10, 50-500 mg of alpha-lipoic acid, 1-5 g of creatine, and 50-200 mg of vitamin E at a daily dose.

[0054] In one embodiment, caffeine is present in the weight management composition as anhydrous caffeine or in a natural source such as green tea or green coffee beans. Anhydrous caffeine can be derived from any suitable source, such as from any of about 60 naturally caffeinated plants, including tea leaves, coffee beans, cocoa beans, yerba mate, guarana berries, guayusa, and yaupon holly. Preferably, the weight management composition contains a daily dose of about 25–1000 mg of caffeine, for example, about 100–250 mg.

[0055] In another embodiment, the weight management composition is substantially caffeine-free. In the substantially caffeine-free weight management composition, naturally caffeine-containing ingredients are provided in a decaffeinated form, such that each decaffeinated ingredient contains, for example, less than 1% caffeine by dry weight. Methods for decaffeination are known in the art.

[0056] According to one embodiment, the weight management composition can be used as a sole, primary, or supplementary source of nutrition. When the weight management composition is used as a sole source of nutrition, the composition will typically contain other essential nutrients required by appropriate food, such as vitamins, minerals, proteins, carbohydrates, fiber, and fats / lipids, as understood by those skilled in the art.

[0057] When a weight management composition is used as a non-sole source of nutrition, it may be formulated with at least one other source of nutrition, including but not limited to: protein, carbohydrates, lipids, fiber, vitamins, minerals, antioxidants, prebiotics, probiotics, phytochemicals, or phytonutrients.

[0058] The protein in a weight management composition comprises any food-grade protein suitable for oral administration to an individual. The protein may be selected from any suitable protein source, including proteins from animal sources, dairy sources, plant sources, insect sources, or any combination thereof. Non-limiting examples of insect protein sources include: cricket protein, locust protein, mealworm protein, earthworm protein, and any combination thereof. Non-limiting examples of animal-derived proteins include: bovine protein, poultry protein, goat protein, lamb protein, poultry protein (e.g., chicken, duck, goose, pheasant, etc.), wild game protein, seafood protein (e.g., fish and shellfish), and any combination thereof. Non-limiting examples of dairy protein sources include: whey protein, whey protein concentrate, whey protein isolate, milk protein concentrate, milk protein isolate, powdered fat and / or non-fat milk, micellar casein, acidic casein, potassium caseinate, calcium caseinate, sodium caseinate, and any combination thereof. Non-limiting examples of plant protein sources include: pea protein, yeast protein, soy protein, corn protein, wheat protein, rice protein, rapeseed protein, peanut protein, soybean protein, lentil protein, and any combination thereof. The protein source may be unhydrolyzed, partially hydrolyzed, or hydrolyzed, and may be in the form of complete proteins, amino acids, or peptides. Non-limiting examples of amino acids may include essential amino acids such as leucine, isoleucine, valine, tryptophan, methionine, threonine, phenylalanine, and lysine, as well as semi-essential amino acids such as histidine and arginine, and non-essential amino acids such as tyrosine, aspartic acid, glycine, alanine, cysteine, arginine, glutamic acid, proline, glutamine, serine, asparagine, taurine, and any combination thereof. Preferably, the protein source is a high-quality protein source that contains at least each essential amino acid. More preferably, the protein source is a high-quality protein source containing an additional amount of leucine. In one embodiment, the composition of the present invention may contain about 0.1 to 99 wt% protein.

[0059] The carbohydrates suitable for weight management compositions comprise any food-grade carbohydrates suitable for oral administration to an individual. Suitable carbohydrates include, without limitation, the following non-limiting examples: rapidly digestible carbohydrates, such as monosaccharides, disaccharides, or polysaccharides (e.g., glucose, fructose, sucrose, dextrose, maltodextrin, and maltose), molasses, honey, maple syrup, corn syrup, high-fructose corn syrup, sugar alcohols (e.g., xylitol, maltitol, erythritol, sorbitol, hydrogenated starch hydrolysate, isomaltulose, and mannitol) or more difficult-to-digest carbohydrates, such as katakuri starch, corn starch, potato starch, kudzu root powder, alginate, xanthan gum, locust bean gum, oat bran, wheat bran, and rice bran, or combinations thereof. In one embodiment, the compositions of the present invention may comprise about 0.1% to 99% carbohydrates by weight.

[0060] Weight management compositions may contain any food-grade fiber source suitable for oral administration to an individual. Suitable fiber sources include, but are not limited to, soluble dietary fibers such as beta-glucan, pectin, xylose, plant gums, inulin, and alginate, and insoluble dietary fibers such as lignin, beta-glucan, xanthan gum, resistant starch, and combinations thereof. Fiber may be included in the composition in an amount that does not adversely affect its function.

[0061] Weight management compositions may contain any food-grade lipid source suitable for oral administration to an individual. Suitable sources of lipids include, but are not limited to, the following: olive oil, safflower oil, rapeseed oil, coconut oil, corn oil, palm oil, palm kernel oil, soybean oil, peanut oil, fish oil, almond oil, sunflower oil, butter, lard, and medium-chain triglycerides, long-chain triglycerides, monoglycerides, diglycerides, cold-water fish (e.g., cod, salmon, tuna, sardines, mackerel, krill, and squid), algae, dark green leafy vegetables, sources of plant and plant seed oils (e.g., flaxseed oil, canola oil, and walnut oil), nuts (e.g., walnuts), and combinations thereof. Lipids may be included in the composition in an amount that does not adversely affect the function of the composition.

[0062] Weight management compositions may contain any food-grade vitamin and mineral source suitable for oral administration to an individual. Suitable vitamins include, but are not limited to, the following: vitamin A, vitamin C, vitamin D, vitamin K, thiamine, riboflavin, niacin, pantothenic acid, pyridoxine, folic acid, cobalamin, biotin, carotenoids (e.g., lutein, beta-carotene, lycopene, and cryptoxanthin), choline, inositol, and combinations thereof, and suitable minerals include, but are not limited to, calcium, phosphorus, selenium, chromium, zinc, molybdenum, iodine, chloride, phosphorus, manganese, fluoride, potassium, iron, copper, magnesium, sodium, and combinations thereof. When used alone or in combination with food, the vitamin content should conform to the recommended daily dose. Vitamins and minerals may be included in the composition in amounts that do not adversely affect the function of the composition.

[0063] Weight management compositions may contain any food-grade antioxidant suitable for oral administration to an individual. Suitable antioxidants include, but are not limited to, citrate monohydrate, vitamin A, vitamin C, folic acid and beta-carotene, iron, copper, butylated hydroxyanisole, butylated benzyl alcohol, propyl gallate, tert-butylhydroquinone, resveratrol, and phytonutrients or phytochemicals (e.g., flavonoids and lignin). Herbs or herb extracts (e.g., oregano, goji berries, dill, thyme, rosemary, and peppermint), tea leaves or tea extracts (e.g., camellia), coffee bean extracts (e.g., medium-bean coffee and small-fruit coffee), brewed coffee or tea or brewed coffee or tea extracts (e.g., oolong tea and Robusta coffee), and other plants or plant extracts (e.g., ginger root) may also be used as sources of antioxidants, as well as any combination of antioxidants. Antioxidants may be included in the composition in an amount that does not adversely affect the function of the composition.

[0064] Weight management compositions may contain any food-grade prebiotic source suitable for oral administration to an individual. Suitable prebiotics include, but are not limited to, dietary fiber and carbohydrate polymers such as cellulose, inulin, gums, trans-galacto-oligosaccharides, fructans, resistant starch, xylooligosaccharides, hemicellulose, pectin, sugar alcohols, beta-glucan, and combinations thereof.

[0065] Weight management compositions may contain any food-grade probiotic source suitable for oral administration to an individual. Suitable probiotics include, but are not limited to, the following: Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus rhamnosus, Lactobacillus gasseri, Lactobacillus salivarius, Lactobacillus bulgaricus, Lactobacillus helveticus, Lactobacillus silivarus, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus casei-like bacteria, Lactobacillus fermentum, Bifidobacterium breve, Bifidobacterium lactis, Bifidobacterium longum, Bifidobacterium bifidum, Bifidobacterium infantis, Bifidobacterium bifidum, Bacillus coagulans, Saccharomyces boulardii, Pediococcus lactis, and combinations thereof.

[0066] Weight management compositions may contain any food-grade phytochemical or phytonutrient suitable for individual oral administration. Suitable phytochemicals or phytonutrients include, but are not limited to, the following: phytosterols, including sterols (e.g., campesterol) and steranols (e.g., sitosterol), soy flavonoids (e.g., genistein and daidzein), garlic and organosulfur compounds (e.g., L-cysteine ​​sulfoxide and γ-glutamyl-L-cysteine ​​peptide), carotenoids (e.g., zeaxanthin, α-carotene, β-carotene, lycopene, β-cryptoxanthin and lutein), resveratrol, curcumin, fiber (e.g., lignin and cellulose), indole-3-methanol and condensation products (e.g., 3,3'-diindolylmethane and 5,11-dihydroindolyl-[3,2-b]carbazole), chlorophyll and chlorophyll isothiocyanates, isothiocyanates (e.g., thioradish and benzyl isothiocyanate) and combinations thereof.

[0067] Prebiotics, probiotics, phytochemicals and phytonutrients may be included in the composition in amounts that do not adversely affect the function of the composition.

[0068] The compositions of the present invention may additionally contain at least one physiologically acceptable excipient. As used herein, the term "physiologically acceptable" refers to food-grade excipients that are therefore acceptable for consumption or administration to mammals. Examples of suitable excipients, not to be construed as limiting, include flavoring agents, sweeteners, anti-caking / flowing agents, emulsifiers, stabilizers, masking agents, coloring agents, preservatives, disintegrants, binders, thickeners, and pH adjusters.

[0069] Non-limiting examples of flavorings include natural or artificial flavorings such as fruit flavorings (e.g., raspberry, orange, apple, pomegranate, mixed berries, lemon, lime, watermelon, strawberry, blueberry, pineapple, coconut, grape, cherry, banana, peach, mango, kiwi, cranberry), sodium sources (e.g., sodium chloride and monosodium glutamate), high-fructose corn syrup, vanilla, chocolate, unsweetened chocolate, honey, molasses, brown sugar, coffee, cocoa, mint, maple, almond, or extracts or combinations thereof. Salty seasonings (e.g., beef, chicken, or vegetable seasonings) may also be used.

[0070] Non-limiting examples of sweeteners include natural sweeteners such as glucose, fructose, sucrose, dextrose, maltose, brown sugar, molasses, honey, maple syrup, corn syrup, high-fructose corn syrup, erythritol, xylitol, sorbitol, isomaltitol, monosaccharide, monosodium glutamate, curculigo orchioides, blazilin, tagatose, and mannitol, as well as artificial sweeteners such as aspartame, acesulfame potassium, cyclohexylsulfamic acid, and sucralose.

[0071] Other non-limiting examples of excipients include: anti-caking or flow agents, such as silicates (e.g., silicon dioxide) and calcium stearate or magnesium stearate; emulsifiers, such as agar, gum, egg yolk, lecithin, monostearate, monosodium phosphate, monoglycerides, diglycerides, and alginate; stabilizers, such as glycerol, agar, gum, alginate, and pectin; masking agents, such as glycerol, sodium chloride, peppermint, limonite, mint, cherry, black licorice, peach, apricot, and raspberry; or sweeteners, such as aspartame or sucrose; coloring agents, such as those suitable for inclusion in food, such as FD&C Blue #1, FD&C Blue #2, FD&C Citrus Red #2, FD&C Green #3, FD&C Red #3, FD&C Red #40, FD&C... &C Yellow #5 and FD&C Yellow #6; preservatives such as butylated hydroxyanisole, butylbenzyl alcohol, ethylenediaminetetraacetic acid, nitrates (e.g., sodium nitrate), sulfites (sodium bisulfite), benzoates (sodium benzoate), sorbates (e.g., sodium sorbate), and sodium chloride; disintegrants such as starch (e.g., potato starch), alginic acid, cellulose and its derivatives, and calcium silicate; binders such as stearic acid, gelatin, sugars and their derivatives, sugar alcohols, polyethylene glycol, and cellulose; thickeners such as polysaccharide-based thickeners such as plant gums, pectin, and starch, or protein-based thickeners such as gelatin, egg white, and collagen; and pH adjusters such as citric acid, ammonium carbonate, ammonium phosphate, calcium carbonate, sodium hydroxide, malic acid, and phosphoric acid. As those skilled in the art will understand, for each type of excipient (e.g., flavoring agent, sweetener, emulsifier, preservative, etc.), a single excipient may be used, or a combination of two or more may be used.

[0072] Weight management compositions can be formulated for oral administration and may be in the form of, for example, solids, semi-solids, liquids, semi-liquids, powders, suspensions, emulsions, solutions, ready-to-drink beverages, gels, strips, pills, tablets, or capsules. As used herein, the terms “oral” or “orally” are intended to include any method of introducing a weight management composition into the digestive tract, including the stomach and small intestine. Examples of oral administration may include administration via the mouth, direct access to the stomach via a feeding tube, access to the stomach via the nose, and access to the small intestine via the nose. In preferred embodiments, the weight management composition is provided in the form of loose powder, strips, or capsules. Loose powder compositions can be reconstituted immediately before consumption in water or any suitable liquid (such as fruit juice, milk, saline, etc.). When provided in loose powder form, the weight management composition may be packaged in individually used containers, packets, or sachets, or in larger bulk containers. When provided in powder form in capsules, any suitable capsules may be used, including capsules containing gelatin and hard hydroxypropyl methylcellulose (also known as hydroxypropyl methylcellulose).

[0073] Weight management compositions can also be administered parenterally, alone or in combination with at least one pharmaceutically acceptable adjuvant, for use in methods according to embodiments of the invention. The term "pharmaceutically acceptable" means acceptable for use in the pharmaceutical and veterinary fields, i.e., without unacceptable toxicity or other unsuitability. Examples of pharmaceutically acceptable adjuvants include diluents, excipients, etc. For general guidance on pharmaceutical formulations, refer to "Remington's: The Science and Practice of Pharmacy," 21st Ed., Lippincott Williams & Wilkins, 2005. The choice of adjuvant depends on the intended route of administration of the composition. In one embodiment of the invention, the composition is formulated for administration by infusion or by subcutaneous or intravenous injection. The composition can be prepared as a sterile and pyrogen-free aqueous solution and optionally buffered or made isotonic. Thus, the composition can be administered in distilled water or, more preferably, in saline, phosphate-buffered saline, or a 5% glucose solution. Creams, lotions, and ointments can be prepared for topical application using suitable matrices such as triglyceride matrices. Such creams, lotions, and ointments may also contain surfactants. Aerosols containing suitable propellant adjuvants can also be prepared. Other adjuvants can be added to the composition regardless of how it is applied; for example, antimicrobial agents can be added to the composition to prevent microbial growth during extended storage. The composition may include a coating or may be encapsulated in a protective material to prevent undesirable degradation by enzymes, acids, or other conditions that may affect its therapeutic activity.

[0074] Weight management compositions may be administered to mammals in need of them in a daily effective amount once or multiple times daily for a duration ranging from one day to a period of time or long-term administration. As used herein, the term "mammal" refers to both human and non-human mammals, such as livestock (cats, dogs, horses, and other livestock). As used herein, the term "daily effective amount" refers to any amount in a mammal that achieves the desired effect without exceeding any amount that could cause adverse side effects. For example, a daily effective amount of weight management composition may be administered once daily, or a daily effective amount of weight management composition may be divided into 2, 3, 4, 5, 6, or more portions and administered daily. In one embodiment, the weight management composition is administered to the individual once daily upon first awakening each morning. The weight management composition may be administered to individuals in need for 1, 2, 3, 4, 5, 6, or 7 days per week, and for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks. In one embodiment, the weight management composition is administered to individuals in need of them long-term. As used herein, the term "long-term" means the application of the weight management composition for at least 2 to 4 months or longer, for example, continuous application of the weight management composition for more than 6 months, at a frequency of at least 2 days per week, and preferably at least 3 days or more per week. In one embodiment, the daily effective dose of the weight management composition is consumed in two doses, one applied in the morning and the other in the afternoon or evening, for 3 months. In another embodiment, the daily effective dose of the weight management composition is consumed in more than three doses, one applied in the morning, the second around noon, and the third in the evening, for 3 months.

[0075] The components of the composition can be administered together as a single composition, or individually in dosage forms that may be the same or different and can be administered simultaneously or at different times. For example, a weight loss agent can be administered in tablet form, while a mitochondrial enhancer can be administered separately in different dosable dosage forms (e.g., capsules). The mitochondrial enhancer can be administered simultaneously with the weight loss agent, or at different times at the same or different frequencies. For example, a weight loss tablet can be administered twice daily, while a mitochondrial enhancer capsule can be administered once or twice daily. In one embodiment, each component of the weight management composition is provided together or separately in capsule form, except for creatine, which is provided in tablet form.

[0076] The weight management composition of the present invention can be used to treat or improve at least one of the following in mammals: weight, body fat, mitochondrial capacity, fatty liver disease, dyslipidemia, oxidative stress levels, BAT activity, and systemic inflammation levels. The term "individual" as used herein refers to a mammal, preferably a human. The method includes administering an effective amount of the weight management composition to the individual. This method can be used to treat any individual, including individuals of any age. The terms "treatment" or "manipulation" as used herein refer to methods that advantageously alter weight, body fat, intrahepatocyte lipid deposition, lipid levels, oxidative stress levels, BAT activity, systemic inflammation levels, and mitochondrial energy production capacity, including the capacity to develop, regulate, reverse, mitigate, or prevent the development of conditions associated with abnormal regulation of weight, body fat, intrahepatocyte lipid deposition, lipid levels, oxidative stress levels, BAT activity, systemic inflammation levels, and mitochondrial energy production capacity. The term "improvement" used in this article for variables related to weight, body fat, intracellular lipid deposition, blood lipid levels, oxidative stress levels, BAT activity, systemic inflammation levels, and mitochondrial energy production capacity refers to an increase or decrease in the health of the variable; that is, an increase or decrease in the variable, either way, is considered to promote health. For example, the treatment will typically achieve at least one of the following: weight loss, increased mitochondrial capacity, reduced intracellular lipid deposition in hepatocytes for the treatment of fatty liver disease, decreased blood lipid levels for the treatment of dyslipidemia, decreased oxidative stress levels, increased BAT activity, and decreased systemic inflammation levels.

[0077] This method is useful for healthy individuals and those who need treatment for one or more of the following: weight, body fat, fatty liver disease, dyslipidemia, oxidative stress levels, BAT activity, systemic inflammation levels, and mitochondrial capacity, such as the elderly, bedridden individuals, hospitalized individuals, and individuals with diseases or conditions that adversely affect one or more of the following: weight, body fat, fatty liver disease, dyslipidemia, oxidative stress levels, BAT activity, systemic inflammation levels, and mitochondrial capacity.

[0078] As used herein, the term "weight" refers to an individual's total body weight or the mass of a specific area of ​​the body. Improved weight is defined as a reduction in an individual's weight by at least about 0.5% compared to before treatment with the compositions of the present invention, preferably by about 1% or more, such as 5%, 10%, 30%, 50%, 70%, or more, or a reduction in the rate of weight gain compared to before treatment by at least about 1% or more, preferably by about 5% or more, such as 10%, 30%, 50%, 70%, 90%, or more. Regarding weight, the compositions of the present invention unexpectedly exhibit a synergistic effect, i.e., the combined effect of the weight-reducing agent and the mitochondrial enhancer results in a weight loss greater than the additive effect of using the weight-reducing agent alone or the mitochondrial enhancer alone. In turn, this will be reflected in other treatments in which the compositions can be used, provided that the improvement in weight and the reduction in body fat promote such treatment.

[0079] As used herein, the term "body fat" refers to an individual's total fat mass or the amount of fat in a specific area of ​​the body. In a healthy weight loss process, most weight loss is due to a reduction in an individual's stored excess fat. Improved body fat is defined as a reduction in an individual's body fat by at least about 0.5% compared to before treatment with the composition of the present invention, preferably by about 1% or more, for example, a reduction of about 0.5%, 5%, 10%, 30%, 50%, 70%, or more. This reduction in body fat before treatment with the composition of the present invention, or a decrease in the rate of increase in body fat compared to before treatment by at least about 1% or more, and preferably by about 5% or more, for example, 10%, 30%, 50%, 70%, 90%, or more.

[0080] As used herein, the term "mitochondrial capacity" refers to the total physiological production capacity of mitochondria to generate cellular energy stores through cellular respiration. This term encompasses the mitochondrial performance of one or more mitochondria and can be used to describe mitochondrial capacity in a specific region (e.g., a particular muscle or organ) or throughout the body. Important indicators of mitochondrial capacity include, but are not limiting, the following non-limiting examples: increased mRNA expression of mitochondrial capacity biomarkers (e.g., PGC1α, COX2, PPARα, HSL, SCHAD, UCP3, PRDM16, CIDEA, and AIPOQ); the number of mitochondria in a tissue (also known as mitochondrial volume density); increased enzymatic capacity expressed in absolute value or relative to the total number of mitochondria measured; the presence of biomarkers of mitochondrial integrity (e.g., absence of deletions, cristae breaks, or polymorphisms); and increased mitochondrial mobility through mitophagy or mitochondrial fission and fusion events (but not excessively). For example, improved mitochondrial capacity refers to the mRNA expression of mitochondrial capacity biomarkers in an individual compared to the present invention group. The mRNA expression of mitochondrial capacity biomarkers in individuals prior to treatment with the composition increases by at least about 0.5%, preferably by about 1% or more, such as 5%, 10%, 30%, 50%, 70%, or higher. Alternatively, in individuals experiencing a decline in the mRNA expression of mitochondrial capacity biomarkers, the rate of decline in the mRNA expression of mitochondrial capacity biomarkers is reduced by at least about 1% or more compared to the rate of decline in the mRNA expression of mitochondrial capacity biomarkers in individuals prior to treatment with the composition of the present invention, and preferably the rate of decline in the rate of mitochondrial capacity loss is reduced by about 5% or more, such as 10%, 30%, 50%, 70%, 90%, or higher. Improvement in mitochondrial capacity can also refer to the normalization of mitochondrial capacity in one or more tissues at the level of healthy individuals.

[0081] As used herein, the term "fatty liver disease" is intended to encompass a range of metabolic fatty liver disorders, ranging in severity from fatty liver (also known as steatosis) to steatohepatitis, progressing to fibrosis / cirrhosis, and potentially liver failure or hepatocellular carcinoma. Fatty liver disease also refers to non-alcoholic fatty liver disease and alcoholic liver disease (ALD). Indicators of the presence or progression of fatty liver disease may include hepatic triglyceride accumulation, liver inflammation biomarkers, hepatic endoplasmic reticulum stress biomarkers, hepatocellular damage or death biomarkers, and liver fibrosis biomarkers. For example, improved fatty liver disease is characterized by a reduction of at least about 0.5% in intracellular lipid deposition in the liver cells of an individual compared to the individual before treatment with the composition of the present invention, preferably a reduction of about 1% or more, such as 5%, 10%, 30%, 50%, 70% or more, or a reduction of at least about 1% or more in the rate of increase of intracellular lipid deposition in the liver compared to the rate of increase of intracellular lipid deposition in the liver cells before treatment, and preferably a reduction of about 5% or more, such as 10%, 30%, 50%, 70%, 90% or more.

[0082] As used herein, the term "dyslipidemia" refers to abnormal levels of lipids in the blood, and this term generally refers to elevated levels of non-HDL cholesterol (including chylomicrons, LDL cholesterol, IDL cholesterol, and VLDL cholesterol), triglycerides, or low levels of HDL cholesterol in the blood. Reducing the total amount of non-HDL cholesterol in the blood or increasing HDL cholesterol typically lowers the risk of or slows the progression of atherosclerotic changes that can lead to coronary artery disease. One of the most accurate methods for diagnosing elevated blood cholesterol is measuring ApoB protein, as this biomarker represents non-HDL protein in the blood, while ApoA1 is commonly used as a biomarker for blood HDL levels. Furthermore, an elevated ApoB / ApoA1 ratio has been shown to be a clinically important biomarker for cardiovascular disease in overweight or obese individuals. For example, improvement in dyslipidemia is a reduction of at least about 0.5% in the level of non-HDL lipids in an individual's blood compared to the level before treatment with the composition of the present invention, preferably about 1% or more, such as a reduction of 5%, 10%, 30%, 50%, 70% or more, or a reduction of at least about 1% or more in the rate of increase of non-HDL lipids in the blood compared to the rate of increase of non-HDL lipids in the blood before treatment, preferably about 5% or more, such as a reduction of 10%, 30%, 50%, 70%, 90% or more. Improvement in dyslipidemia can also refer to an increase of at least about 0.5% in the amount of HDL cholesterol in an individual compared to the individual's HDL cholesterol level before treatment with the composition of the present invention, preferably an increase of about 1% or more, such as 5%, 10%, 30%, 50%, 70% or higher, or a decrease in the rate of decrease in the amount of HDL cholesterol in an individual experiencing a decrease in the amount of HDL cholesterol compared to the rate of decrease in the amount of HDL cholesterol in an individual before treatment with the composition of the present invention, preferably a decrease of about 5% or more, such as a decrease of 10%, 30%, 50%, 70%, 90% or higher.

[0083] As used herein, the term “oxidative stress” refers to the amount of free radicals or free radical-generating agents present in the body’s circulation and throughout the body. Oxidative stress is known to induce modifications that alter the function of proteins, lipids, DNA, and other cellular components. Long-term elevated levels of oxidative stress have been associated with and have been shown to exacerbate obesity and obesity-related comorbidities such as insulin resistance, dyslipidemia, heart disease, and fatty liver disease. Oxidative stress levels are typically assessed by measuring biomarkers of oxidatively modified cellular products, such as protein carbonyl groups and lipid peroxides (e.g., trans-4-hydroxy-2-nonenal (4-HNE)). For example, improved oxidative stress levels are defined as a reduction in 4-HNE protein levels in an individual by at least about 0.5% or more compared to pre-treatment levels with the compositions of the present invention, preferably by about 1% or more, such as 5%, 10%, 30%, 50%, 70% or more, or a reduction in the rate of increase of 4-HNE protein levels by at least about 1% or more compared to pre-treatment levels with the compositions of the present invention, preferably a reduction in the rate of increase of 4-HNE protein levels by about 5% or more, such as 10%, 30%, 50%, 70%, 90% or more.

[0084] As used herein, the term “BAT activity” refers to the total thermogenic activity of brown or beige adipocytes in an individual, or the thermogenic activity of brown or beige adipocytes in any one or more regions (e.g., one or more brown or beige adipocytes in an adipose tissue deposit). Brown or beige adipose tissue is known to increase energy expenditure by increasing oxidative phosphorylation unrelated to ATP production, resulting in the release of heat in the form of heat. Beige adipocytes are generally considered to be white adipocytes that have undergone differentiation and transformation, exhibiting increased “brown” characteristics, such as higher mitochondrial density and mitochondrial uncoupling capacity. Three common approaches to improving BAT activity include: 1) converting one or more white adipocytes in a person to beige adipocytes; 2) neoformation of beige adipocytes from adipogenic progenitor cells; and 3) increasing the thermogenic activity of existing brown adipocytes. BAT activation is typically assessed by measuring the mRNA expression or protein levels of BAT biomarkers such as UCP3, PRDM16, CIDEA, PPARα, and PGC1α. For example, improved BAT activity means that the mRNA expression level of the BAT biomarker in an individual is increased by at least about 0.5% compared with the mRNA expression of the BAT biomarker in the individual before treatment with the composition of the present invention, preferably by about 1% or more, such as 5%, 10%, 30%, 50%, 70% or higher, or in individuals experiencing a decrease in the mRNA expression of the BAT biomarker, the rate of mRNA expression of the BAT biomarker is reduced by at least about 1% or more compared with the rate of decrease in the mRNA expression of the BAT biomarker in the individual before treatment with the composition of the present invention, and preferably in individuals where the rate of mRNA expression of the BAT biomarker is reduced by about 5% or more, such as 10%, 30%, 50%, 70%, 90% or higher.

[0085] As used herein, the term “systemic inflammation level” refers to the amount of inflammation present in the body’s circulation and tissues. While acute inflammation in response to noxious events is considered beneficial, chronic low-grade inflammation is generally considered detrimental and may be associated with the development of other obesity-related chronic diseases. Systemic inflammation levels are typically assessed by measuring the mRNA expression or protein levels of circulating pro-inflammatory biomarkers, such as C-reactive protein (CRP), interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNFα). Other common biomarkers of systemic inflammation include pro-inflammatory cytokines such as IL-1β, IL-12, and IL-18; chemokines such as CCL-8, CCL2, CCL3, CCL4, CCL5, CCL11, and CCL-10; and growth factors such as GM-CSF, PDGF, TGF-β, and VEGF. For example, improved systemic inflammation levels are defined as a reduction in the mRNA expression of inflammatory biomarkers in an individual by at least about 0.5% compared to the mRNA expression of inflammatory biomarkers before treatment with the composition of the present invention, preferably by about 1% or more, such as 5%, 10%, 30%, 50%, 70% or higher, or a reduction in the rate of increase in mRNA expression of inflammatory biomarkers compared to the mRNA expression rate of inflammatory biomarkers before treatment with the composition of the present invention, preferably a reduction in the rate of increase in mRNA expression of inflammatory biomarkers by about 5% or more, such as 10%, 30%, 50%, 70%, 90% or higher.

[0086] In another embodiment, the weight management composition of the present invention can be used in methods of treating obesity, and can also treat one or more obesity-related comorbidities in an individual, such as fatty liver diseases (e.g., steatosis, steatohepatitis, and cirrhosis), cardiovascular diseases (e.g., coronary artery disease and arrhythmia), type 2 diabetes, hypertension, dyslipidemia (e.g., high LDL cholesterol, low HDL cholesterol, high triglycerides), gallbladder disease, osteoarthritis, sleep apnea, asthma, chronic kidney disease, and depression. The method includes administering a weight management composition comprising a weight-loss agent and a mitochondrial enhancer to the individual.

[0087] In another embodiment, the method of promoting individual weight management, reducing weight and body fat and treating obesity in the present invention may advantageously include administering a weight management composition to an individual who also engages in regular exercise.

[0088] The term "exercise" refers to any exercise, including endurance exercise, high-intensity interval training (HIIT), resistance exercise, etc., such as exercise and combinations thereof that achieve a working level of at least about 3-6 metabolic equivalents (METS) (e.g., any combination of endurance exercise, HIIT, or 50% of the maximum repetition value (resistance exercise)). METS is the energy expenditure of a physical activity or exercise, defined as the ratio of an individual's metabolic rate (and therefore energy expenditure rate) to the basal metabolic rate during a particular physical activity. In a preferred embodiment, exercise is performed regularly. Regular exercise means a duration of at least one month, preferably at least three times a week, preferably a chronic exercise lasting for 2, 4, or 6 months or longer, for at least 30 minutes continuously each day, preferably 45 minutes or longer, such as 60 minutes or longer, or 75-90 minutes or longer. Exercise may include endurance activities such as brisk walking, jogging, running, dancing, swimming, cycling, sports, interval training, resistance exercise, etc. Interval training refers to repetitive exercise, which can be performed at high or low intensity as long as the minimum METS requirement is met. High-intensity interval training (HIIT) will include activities such as sprints (e.g., sprints lasting 10 seconds to 4 minutes), followed by recovery time (e.g., 10 seconds to 4 minutes). The term "resistance exercise" refers to weight training or other resistance exercises (plyometrics, hydraulic presses, etc.) performed in sets of repetitions (e.g., 8-15 repetitions) with resistance at least 50% of a repetition's maximum, followed by recovery between sets for a duration sufficient to meet the minimum METS requirements. A repetition's maximum is the maximum voluntary contraction intensity of a single movement, to which a second movement is impossible.

[0089] The weight management composition can be applied at any time relative to exercise, i.e., before, during, or after exercise, or any combination thereof. In one embodiment, the weight management composition is applied to the individual immediately after exercise.

[0090] Unless otherwise indicated, as will be understood by those skilled in the art, the definitions and implementations described in this and other sections are intended to apply to all implementations and aspects to which this application applies.

[0091] Example

[0092] Example 1: The weight management composition improves body weight, body fat mass, and mitochondrial function.

[0093] According to one embodiment of the present invention, it is determined whether a weight management composition comprising a weight loss agent and a mitochondrial enhancer can: 1) reduce weight and body fat and improve mitochondrial capacity; and / or 2) enhance exercise-regulated weight, body fat and mitochondrial capacity, by administering the weight management composition or one of several control compositions to mice fed a high-fat diet (HFD) and allowing them to exercise or remain sedentary for 30 days.

[0094] All experiments were approved by the McMaster University Animal Ethics Committee and conducted in accordance with appropriate Canadian guidelines for animal research. Sixty C57 / B16 diet-induced obese mice were ordered from Jackson Laboratories and placed on HFD (Teklad#TD.06414) containing 60% fat-based energy at week 6, and fed freely. At approximately 12 weeks of age, the mice were divided into experimental groups and normalized to average body weight. Each experimental group was fed one of the following HFDs containing 60% fat energy: Group 1 was fed an HFD control (referred to as the HFD control; energy density 5.1 kcal / g); Group 2 was fed an HFD containing a weight-loss agent (referred to as the WL-only diet; energy density 5.1 kcal / g, and containing the following weight-loss agents in amounts: 0.25 wt% green tea extract, 0.13 wt% black tea extract, 0.25 wt% green coffee bean extract, 0.25 wt% conjugated linoleic acid, and 0.005 wt% trichosamine); Group 3 was fed a diet containing mitochondrial... Group 2 was fed a weight-loss agent-containing HFD (referred to as ME-only food; energy density 5.0 kcal / g, and mitochondrial enhancer containing the following amounts: 1 wt% beetroot juice extract, 0.25 wt% coenzyme Q10, 0.1 wt% alpha-lipoic acid, and 1 wt% creatine (by weight), plus an additional 1000 IU / kg of vitamin E), while Group 4 was fed a weight-loss agent-containing HFD (referred to as weight management combination A food), with an energy density of 5.0 kcal / g, and containing the same amount of weight-loss agent and mitochondrial enhancer as Group 2. Group 3 received the same amount of mitochondrial enhancer. Then, 10 mice from each of groups 1-4 were housed in standard microisolation cages and fed their respective diets for 30 days. To assess the effect of weight management combination A diet on exercise, group 5 (10 mice) was fed weight management combination A diet but housed individually in cages equipped with exercise wheels to allow for voluntary exercise, and additionally exercised on a treadmill at 15 m / min for 45 minutes three times a week. As a further control, group 6 (10 mice) was fed HF diet. Group D was a control group and underwent the same confinement and exercise as Group 5 to provide a reference for the effect of exercise alone on mice fed HFD. Finally, Group 7 mice (comprising 10 C57 / Bl6 mice from Jackson Laboratory, catalog number 000664) were fed a standard mouse diet (designated Chow diet, energy density 3 kcal / g, Envigo (food number 8640)) in micro-isolation cages for 30 days from 0 to 12 weeks as a third control group, demonstrating the effect of a healthy diet on body composition.

[0095] Baseline testing was performed on all mice 7 days before the introduction of the experimental diet (i.e., day -7). Baseline testing included the following measurements: body weight, relative fat mass and muscle mass, grip strength, motor coordination, and maximum running ability. On day 0, the experimental diet was introduced to all mice, and two exercise groups were placed in walking wheel cages and began a treadmill exercise program. Body weight was measured daily throughout the study, approximately daily, along with food intake. After 24 days of receiving the experimental diet, each group continued with their own diet, and baseline assessments were repeated over a period of one week as endpoint indicators. On day 31, mice were anesthetized with isoflurane, euthanized by exsanguination, and tissues were collected.

[0096] Relative fat mass and muscle mass were quantified and normalized to body weight using a time-domain NMR whole-body composition analyzer (minispec LF90II, Bruker, Massachusetts, USA). Maximum exercise capacity was measured by exercising mice on a treadmill at an initial speed of 10 m / min, increasing the speed by 1 m / min every minute until exhaustion. Motor coordination, grip, and balance were assessed using a rotating footplate apparatus (Harvard Equipment, Massachusetts).

[0097] result

[0098] To determine the effectiveness of a weight management composition containing a weight loss agent and a mitochondrial enhancer, weight was recorded during a 24-day period of dietary supplementation. Figure 1 As expected, mice fed the HFD control (Group 1) continued to gain weight throughout the study period, while this HFD-induced weight gain decreased in Groups 2 and 3. Surprisingly, after 24 days of supplementation, mice fed the weight management combination A diet (Group 4) had a lower mean weight than those fed only the W diet (Group 2) or only the ME diet (Group 3), indicating that the weight management combination exhibited a synergistic or greater than additive weight loss effect. To assess the interaction between the weight management combination A diet and exercise effects, Group 2, fed the diet, underwent a 30-day exercise program. Although mice in Group 6 were spared any HFD-induced weight gain, Group 5 showed significantly greater weight loss, reaching a healthy weight comparable to that of mice fed the Chow diet (Group 7) by Day 6 of supplementation and maintaining that ideal weight for the remainder of the study. To obtain another perspective on weight loss, body composition was also measured by MRI. The relative fat mass in Group 1 increased over time, as expected for the endpoint measurement. Figure 2A). Although mice in groups 2 and 3 showed little or no increase in body fat during the treatment period, mice in group 4 experienced a decrease in relative body fat despite continued HFD feeding. This demonstrates that synergistic weight loss can be achieved by combining diet and exercise with managed weight management combination A, with mice in group 5 showing a 53% reduction in endpoint body fat and mice in group 6 showing a 27% reduction. Groups 1–3 experienced relatively small reductions in muscle mass ( Figure 2 B). Importantly, this loss of muscle mass was avoided in groups 4–7. Tissue weights were recorded immediately after collection to further understand how the experimental diet affected body composition. Consistent with previous findings, the relative weight of the abdominal fat pad was lower in groups 2 and 3 compared to group 1, and further reduced in group 4. Figure 3 A). Furthermore, the relative intra-abdominal fat pad weight in group 5 was 68% lower than that in the sitting HFD control group 1, while group 6 was only 43% lower than the same sitting control group. Conversely, the liver ( Figure 3 B) Skeletal muscle Figure 3 C and 4A), heart ( Figure 4 B) Pancreas ( Figure 4 C) or BAT ( Figure 4 The relative weights of D) were not substantially different between the two groups.

[0099] To assess whether any changes in these weight and fat percentages were due to appetite suppression or preferential consumption of any of the experimental food compositions, food intake was monitored. Figure 5 As shown, the food intake of the sedentary mice in groups 1–4 was similar. As expected, the mice in groups 5 and 6 ate 25% more food than the sedentary mice due to the greater energy expenditure from exercise. Similarly, although the mice fed Chow food ate the most among all groups, this was also expected, as Chow food has 40% less energy density than HFD.

[0100] To assess the impact of food on bodily functions, a maximum exercise capacity test was conducted. Figure 6 A) to determine how long mice could run at gradually increasing speeds, and a wheel function test was performed. Figure 6 (B) To quantify motor coordination, balance, and grip. During the supplementation period, mice in groups 1 and 2 showed decreased motor and wheeled lobe abilities, while mice in groups 3 and 4 were unaffected by this HFD-induced performance impairment. Consistent with the training effects of the exercise program, mice in groups 5 and 6 showed significantly improved motor and wheeled lobe abilities at the endpoint measurement compared to baseline.

[0101] These data indicate that the weight maintenance composition effectively improves weight maintenance in overweight or obese individuals.

[0102] Example 2: An alternative form of the weight management composition improved body weight, body fat, and mitochondrial function.

[0103] To confirm that alternative implementations of the weight management composition could similarly reduce weight and body fat and increase mitochondrial capacity as observed in Example 1, a second study was conducted in which HFD-fed mice were given a diet containing the three individual formulations for weight management, combined with exercise or inactivity (medium) for one month.

[0104] All experiments were approved by the McMaster University Animal Ethics Committee and conducted in accordance with appropriate Canadian animal research guidelines. Seventy-two C57 / B16 diet-induced obese mice were ordered from the Jackson Laboratory and placed on HFD (Teklad#TD.06414) containing 60% fat energy at 6 weeks of age and fed freely. At approximately 12 weeks of age, the mice were divided into experimental groups and normalized to mean body weight. Each experimental group was fed one of the following HFDs containing 60% fat energy: Group 8 was fed an HFD control (referred to as HFD control food; energy density 5.1 kcal / g); Group 9 was fed the weight management combination A food of Example 1 (referred to as weight management combination A food; energy density 5.0 kcal / g and containing the following weight-loss agents: 0.25 wt% green tea extract, 0.13 wt% black tea extract, 0.25 wt% green coffee bean extract, 0.25 wt% conjugated linoleic acid, and 0.005 wt% trichosamine, as well as the following... The following amounts of mitochondrial enhancers were provided: 1 wt% beetroot juice extract, 0.25 wt% coenzyme Q10, 0.1 wt% alpha-lipoic acid, and 1 wt% creatine, plus 1000 IU / kg of vitamin E; Group 10 was fed another weight management composition (referred to as Weight Management Combination B food; energy density 5.0 kcal / g) and contained the following weight loss agents: 0.375 wt% green tea extract, 0.25 wt% green coffee bean extract, 0.25 wt% conjugated linoleic acid, and 0.005 wt% trichodin, as well as the following amounts of mitochondrial enhancers, which contained... The following amounts were added: 1 wt% beetroot juice extract, 0.25 wt% coenzyme Q10, 0.1 wt% alpha-lipoic acid, and 1% creatine, along with an additional 1000 IU / kg of vitamin E; the second alternative weight management composition of group 11 (referred to as weight management composition C food) was fed, with an energy density of 5.0 kcal / g, and containing the following amounts of weight loss agents: 0.375 wt% green tea extract, 0.25 wt% green coffee bean extract, and 0.005 wt% trichosamine, and the following amounts of mitochondrial enhancers: 1 wt% beetroot juice extract, 0... The diet consisted of 0.25 wt% coenzyme Q10, 0.1 wt% alpha-lipoic acid, and an additional 1000 IU / kg of vitamin E. Mice in groups 8–11, consisting of 12 mice per group, were then housed separately in standard microisolation cages and fed their own diets for one month. To further evaluate the effect of the weight management combination A diet on exercise, a 13th group of mice (comprising another group of 12 mice) was fed the weight management combination A diet, but housed individually in cages equipped with exercise wheels to allow for voluntary, unrestricted exercise. The mice were then exercised on a treadmill three times a week at a speed of 15 m / min for 45 minutes each time.As a further control, Group 12, consisting of 12 mice, was fed the HFD control diet and received the same feeding and exercise protocol as Group 13 to provide a reference for the effect of exercise alone on mice fed HFD. Finally, Group 14 (Jackson Lab, catalog number 000664), consisting of 12 C57 / Bl6 mice, fed the standard mouse chow diet (designated as Chow diet, energy density 3 kcal / g; Envigo, food number 8640) for 30 days from 0 to 12 weeks in microisolated cages as a third control to demonstrate the effect of a healthy diet on body composition.

[0105] All mice underwent baseline testing starting 7 days before the introduction of the experimental diet (i.e., day -7). Baseline testing included the following measurements: body weight, relative fat mass, muscle mass, and maximal exercise capacity. On day 0, all mice were introduced with the experimental diet, and two exercise groups were placed in walking wheel cages and began a treadmill exercise program. Body weight was measured daily and food intake weekly throughout the study. After one month of treatment with the experimental diet, each group was then fed their own diet, and baseline assessments were repeated as weekly endpoints. One week after the one-month treatment period, mice were anesthetized with isoflurane, euthanized by exsanguination, and tissues were collected. Relative fat mass, muscle mass, and maximal exercise capacity were measured as described above.

[0106] Following tissue harvest, mitochondrial respiration in permeable quadriceps femoris muscles was assessed using a high-resolution respiration assay (Oroboros Oxygraph-2k, Oroboros Instruments, Corp; Innsbruck, Australia). Oxygen consumption in state 2 supported by complex I was measured under conditions of 5 mM pyruvate, 2 mM malate, and the absence of ADP, providing an indicator of the uncoupling of mitochondrial substrate oxidation and ATP production. Submaximal oxygen consumption in state 3 supported by complexes I and II was measured in the presence of 500 μM ADP, 2 mM malate, and 5 mM pyruvate, to simulate respiration supported by complex I via NADH generation.

[0107] The following antibodies from 5% milk of TBS were used to evaluate the proteins p62 and 4-HNE in the quadriceps femoris muscle: p62 (CellSignalling, catalog number 51145) and hydroxynonenal (Abcam, catalog number ab46545). RNA was isolated from the liver using the RNeasy mini kit (Qiagen), normalized to 2 μg, and reverse transcribed into cDNA using the SuperScript Vilo cDNA Synthesis Kit (Life Technologies). The viia7 system (Thermofischer Scientific) was used with FAST SYBR Green (Life Technologies) for quantitative real-time PCR to assess the types of mRNA in the liver. RNA was isolated from the peritoneal reservoir of white adipose tissue using the Trizol / chloroform method. RNA (aqueous phase) was purified using the EZNATotal RNA Kit 1 (Omega Bio-Tek, Norcross, GA, USA) according to the manufacturer's instructions. RNA was then purified using a high-capacity cDNA reverse transcription kit (…). VILO TM Reverse transcription was performed on the samples using Master Mix (Invitrogen, catalog number 11755050). Liver triglycerides were quantified using a commercially available kit (Abcam, ab65336) following the manufacturer's instructions. Lipid droplet staining was assessed in frozen liver sections using Oil Red O. Briefly, liver sections were washed in propylene glycol and exposed to an Oil Red O solution prepared in isopropanol. The sections were then washed again in propylene glycol, counterstained with hematoxylin, and fixed in an aqueous medium. Hepatic steatosis was qualitatively scored by a trained pathologist according to the following criteria: 0 = none, few to few affected cells; 1 = mild, few to up to 50%; 2 = moderate, 50% few macroglobulins; 3 = widespread, numerous scattered macroglobulins. Serum alanine aminotransferase (ALT) activity was assessed using a commercially available kit (Cayman Chemical, 700260) following the manufacturer's instructions. Serum ApoB levels were quantified using a commercially available ELISA (Abcam, ab20737). Serum samples were diluted 1:5000 and administered according to the manufacturer's instructions. Serum ApoA1 levels were quantified using a commercially available ELISA (Abcam, ab238260). Serum samples were diluted 1:50,000 and administered according to the manufacturer's instructions. Serum PCSK9 levels were quantified using a commercially available ELISA (R&D Systems, MCP900). Serum samples were diluted 1:400 and administered according to the manufacturer's instructions.

[0108] To measure the COX / CS ratio, quadriceps muscle was homogenized in Lysing Matrix D tubes (MP Biomedicals, Solon, Ohio, USA) using a FastPrep-24 tissue and cell homogenizer (MP Biomedicals, Solon, Ohio, USA) at a speed of 4.0 m / s for 5 cycles of 5 seconds each, with the samples placed on ice for 5 minutes between cycles. The samples were then homogenized in 20-fold volume buffer containing 70 mM sucrose, 220 mM mannitol, 10 mM HEPES, 1 mM EGTA, and a protease inhibitor (Laval, Quebec, Canada). (Roche Applied Science). To determine the maximum activity of citrate synthase, 15 μl of muscle homogenate was added to a cuvette containing: 825 μl of 0.1 M Tris buffer (pH 8.0), 100 μl of 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB, 0.5 mg / mL Tris buffer), and 10 μl of acetyl-CoA (6 mg / mL Tris buffer). The cuvette was heated to 37 °C, and 50 μL of oxaloacetic acid (6.1 mg / mL Tris buffer) was added to initiate the reaction. The absorbance was recorded at 412 nm for 120 seconds, and the slope between 30 and 90 seconds was recorded. For COXIV activity, sodium bisulfite was used to reduce oxidized cytochrome c (Sigma C7752) in 0.05 M potassium phosphate buffer (KH2PO4, pH 7.4). Add 20 μL of muscle homogenate to 955 μL of 0.05 M potassium phosphate buffer and 30 μL of reduced cytochrome c in a cuvette heated to 37 °C. Measure the oxidation rate of reduced cytochrome c at 550 nm for 3 minutes at 37 °C.

[0109] result

[0110] As expected, the body weight of mice fed the HFD control (group 8) continued to increase over a one-month period, increasing by 31% compared to their body weight on day 0. Figure 7 Similar to the findings in Example 1, mice in Group 9 fed with Weight Management Combination A food showed a significant decrease in body weight after one month of supplementation, compared to Group 8. Importantly, despite one month of HFD feeding, mice in Groups 10, 11, and 12 were protected from similar HFD-induced weight gain, with reductions in starting body weight of 2%, 3%, and 4%, respectively. As shown in Example 1, mice fed with Weight Management Combination A food, except for those exercising (Group 13), experienced the greatest weight loss (13%) among all groups and maintained their weight similar to mice fed with Chow food (Group 14). For a second measurement of body weight, fat was measured by MRI. Figure 8A) and muscle mass ( Figure 8 B). As predicted by the weight findings, the relative fat mass of group 8 increased by 68% compared to the starting amount, while the fat mass of groups 9–11 showed almost no increase. Compared to the starting amount, the relative fat mass of mice in group 12 decreased by 19%, and that of mice in group 13 decreased by 46%. No significant differences in muscle mass were observed between any of the HFD groups, except that the relative muscle mass in group 8 decreased by 12% compared to the starting amount. For the third measurement of body composition, tissue weight was measured. In groups 3 and 12 of the weight management combination diet (groups 9–11), the relative intra-abdominal fat store weight in each group was 29–39% lower than that in the HFD control group 8, while the intra-abdominal fat in group 13 of the exercise and weight management combination diet A was 63% lower than that in group 8. Figure 9 A). Liver function between groups ( Figure 9 B) Skeletal muscle Figure 9 C and 10A), heart ( Figure 10 B) Pancreas ( Figure 10 C) and BAT ( Figure 10 The weights of D) were comparable, with the exception of group 8, whose weights were lower relative to the weights of the liver, skeletal muscle, and heart. To assess the effect of the weight management composition on aerobic exercise capacity, at baseline ( Figure 11 A) and endpoint ( Figure 11 B) Exercise capacity testing was conducted. After a one-month experimental period, the maximum running distance of group 8 decreased by 47%. Groups 9–11 experienced reductions of 29%, 31%, and 7%, respectively, indicating that they further prevented the negative effects of HFD. Groups 12 and 13 were completely unaffected by the decline in exercise capacity caused by HFD. These findings suggest that the weight management composition is effective in improving weight management.

[0111] High-resolution oxygen consumption measurements were obtained from the quadriceps femoris muscle to assess skeletal muscle mitochondrial capacity in mice administered the weight management composition. State 2 respiration supported by Complex 1 was first measured in the absence of ADP to provide an indicator of uncoupled respiration. Figure 12 A). Compared to the HFD control group 8, mice in group 14 fed with the Chow diet showed a 45% reduction in free oxygen consumption. Surprisingly, each group, which received a weight management combination diet (groups 9–11 and 13), exhibited a reduction in uncoupled oxygen consumption compared to group 8. Next, submaximal oxygen consumption in state 3 supported by complexes I and II was measured to determine the ability of skeletal muscle mitochondria to perform cellular respiration in the presence of fuel substrates. Similar to uncoupled respiration, ADP-stimulated oxygen consumption was lower in group 14 fed with the Chow diet than in the HFD control group 8, and each group receiving a weight management combination diet (groups 9–11 and 13) had a respiratory rate comparable to that of group 14 fed with the Chow diet. Figure 12 B). Another method for measuring skeletal muscle mitochondrial volume determined the ratio of cytochrome activity to the enzyme activities of oxidase IV (the final enzyme in the electron transport chain) and citrate synthase (a biomarker of mitochondrial density). Figure 12 C). Compared with the HFD control group 8, all groups had lower ratios of cytochrome relative to oxidase IV and citrate synthase activity, with group 14 showing the lowest ratio. Overall, these measurements of skeletal muscle mitochondrial function suggest that HFD induces a compensatory upregulation of skeletal muscle mitochondrial activity, and that the weight management composition protects HFD-fed mice from these changes to maintain mitochondrial function similar to that of healthy Chow-fed mice.

[0112] To evaluate the effect of the weight management composition on mitochondrial capacity in adipose tissue, the mRNA expression of genes crucial for mitochondrial function and lipid oxidation was measured in white adipose tissue. PGC1α, a transcriptional coactivator, is considered one of the major promoters of mitochondrial biogenesis. Compared to group 8, PGC1α expression increased approximately 4-fold in groups 9, 11, and 12. Interestingly, PGC1α expression increased 6.0-fold and 6.4-fold, respectively, in groups 13 and 14. Figure 13 A). COX2 is one of the subunits of citrate synthase and is a biomarker of mitochondrial density, which was lowest in the HFD control group 8. Figure 13 B). In mice fed a weight management diet or exercise regimen, COX2 expression levels increased to levels equal to or greater than those observed in Chow-fed mice. PPARα, HSL, and SCHAD are three key genes that collectively promote the breakdown of stored glycerides into fatty acid chains, tissue uptake of fatty acids, and oxidation of fatty acids in mitochondria. Compared to group 14 fed a Chow diet, PPARα ( Figure 13 C), HSL Figure 13 D) and SCHAD Figure 13 The expression of E) was significantly reduced. Similar to the pattern of mitochondrial biogenesis genes described above, the mRNA expression levels of these genes were elevated in mice that were fed a weight management diet or exercised at levels equal to or greater than those observed in Chow-fed mice. These findings suggest that the mitochondrial capacity of white adipose tissue was improved in mice administered the weight management composition, thereby promoting the use of stored fat for energy expenditure and weight maintenance.

[0113] Increased mitochondrial abundance and activity in white adipose tissue indicate transdifferentiation or browning into beige adipose tissue with higher metabolic activity. In addition to the increased gene expression of PGC1α and PPARα, typical genes of the browning pathway, as described above, the expression of other beige adipose tissue biomarkers was assessed. Compared to the HFD control group 8, uncoupling protein 3 (UCP3) expression was 53% higher in group 14 fed a Chow diet, and 2.9 to 4.7 times higher than in mice fed a weight management combination diet (groups 9, 11, and 13). Figure 14 A). Compared to the lower levels in the HFD control group 8, similar to UCP3, and compared to the browning biomarker PRDM16 in mice given one of the weight management diet combinations, exercise, or a chow diet. Figure 14 B), CIDEA Figure 14 C) and ADIPOQ Figure 14 Gene expression in D) was elevated. These findings suggest that, in addition to observed enhanced lipid oxidation and mitochondrial capacity, the weight management composition also induces browning in white adipose tissue. This enhanced browning is desirable for weight management because it can be expected to increase thermogenesis, thereby promoting energy expenditure from fat storage.

[0114] To determine whether the weight management composition had an effect on oxidative stress, the amount of trans-4-hydroxy-2-nonenal (4-HNE) in skeletal muscle was measured. 4-HNE is a product of lipid peroxidation and a potent biomarker of oxidative stress. Compared to group 14 fed with Chow food, the control group 8 fed with HFD had 29% higher levels of 4-HNE. Figure 15 A). Surprisingly, compared to group 8, the levels of 4-HNE were also reduced by 18% to 37% in mice receiving a weight management diet or exercise (groups 9 and 11–13). Oxidative stress is known to oxidatively damage cellular components and promote the degradation of those cellular materials via the autophagy pathway. p62 accumulation is an indicator of oxidative stress and the amount of cellular components targeted for degradation via the autophagy pathway. Based on the 4-HNE results, p62 abundance was reduced by 30% to 49% in mice receiving a weight management diet, exercise, or a chow diet. Figure 15 B). These results indicate that the weight management composition is effective in improving oxidative stress.

[0115] To determine the effect of the weight management composition on dyslipidemia, serum ApoB and ApoA1 levels were measured. Figure 16As expected, the ApoB / ApoA1 ratio in group 8, fed with HFD, was 59% higher than that in group 14, fed with Chow food. Surprisingly, groups 11 and 12 prevented the HFD-induced increase in ApoB / ApoA1 levels. PCSK9 is an enzyme that increases LDL cholesterol levels by degrading the LDL receptor protein required to transport LDL to tissues. Serum PCSK9 concentrations in group 8 were 24% higher than those in group 14, fed with Chow food. Figure 16 D). Conversely, mice fed a weight-management diet and exercise (groups 11 and 12) had serum PCSK9 levels approximately 50% lower than those in group 14. A protective effect against HFD-induced elevations in hepatic PCSK9 mRNA expression was also observed in groups 11 and 12. Figure 16 E). Supporting this observation, both weight management and exercise similarly protected mice from HFD-induced increases in hepatic SREBP1 and SREBP2 mRNA expression, two major promoters of cholesterol, fatty acid, triglyceride, and phospholipid synthesis. Figure 16 E). These findings suggest that weight management compositions can effectively treat dyslipidemia by improving blood lipid levels.

[0116] To assess whether the weight management composition had any impact on liver health, several biomarkers of fatty liver disease were measured. The amount of triglycerides in the liver of group 8 fed HFD was 3.2 times higher than the quantified triglyceride level in group 14 fed Chow. Figure 17 Conversely, Group 12 (exercise) and Group 11 (weight management combination C food) both showed even lower liver triglyceride levels than Group 14. This observation was further confirmed by trained pathologists through visual inspection of the weight management combination, which reduced liver triglycerides and produced a protective effect against the development of fatty liver. Pathologists provided steatosis scores on Oil Red O-type liver sections for each group. Figure 17 B). Serum alanine aminotransferase (ALT) levels are clinically used as an indicator of hepatocellular injury or death. Compared to group 14 fed Chow food, serum ALT levels in group 8 fed HFD were 2.9-fold higher, while they remained unchanged in groups 11 and 12. Figure 17C). To investigate the potential causes of excessive lipid accumulation in the livers of HFD-fed mice and the presence of normal lipid levels in HFD mice supplemented with a weight management composition, the mRNA expression levels of key liver proteins were assessed. SREBP1, SREBP2, ADRP, and HNF1α are four key genes regulating liver lipid levels. Compared to group 14, the mRNA expression of all four genes was significantly increased in group 8, and for each protein, group 11 showed decreased mRNA expression levels consistent with group 12, which was undergoing routine exercise. Figure 16 E and 18A). The unfolded protein response (UPR) occurs in response to increased endoplasmic reticulum stress, which may be induced by and further promote hepatocyte injury. GRP78, sXBP1, IRE1α, ATF4, PERK, and CHOP are six major genes affecting the UPR and can guide apoptosis during prolonged endoplasmic reticulum stress. Compared with group 14 fed a Chow diet, the mRNA expression of each UPR protein was 2 to 5.3 times higher in the livers of mice fed HFD. Figure 18 B). Routine exercise reduced the HFD-induced increase in UPR markers in group 12, a protective effect reflected in group 11 when fed the weight management combination C diet. Casp1, Casp3, Casp7, Casp9, and PARP1 are five key genes that are promoters of apoptosis, pro-apoptosis, necroptosis, and inflammation, which initiate and influence programmed cell death. Similar to the patterns observed in lipid accumulation and endoplasmic reticulum stress genes, the mRNA expression of these programmed cell death proteins was significantly elevated in the liver of group 8, while decreasing to normal values ​​in groups 11 and 12. Figure 19 A). Inflammation and hepatocellular death are two hallmarks of the second stage of fatty liver disease (called steatohepatitis). Compared with group 14, the hepatic mRNA expression levels of two key regulators of the inflammatory cascade, TNFα and IL-1β, were 3.4 to 5.8 times higher in group 8. Figure 19 B). Conversely, the levels of these inflammatory markers were the same as or close to those in healthy mice fed a Chow diet in groups 11 and 12. Chronic inflammation is associated with the development of liver fibrosis, a marker of stage III fatty liver disease. TGFβ and FN1 are two major genes associated with the development of liver fibrosis. Similar to inflammatory genes, the expression of liver fibrosis markers was significantly elevated in group 8, while levels were reduced or near-elusive in mice fed a Chow diet in groups 11 and 12. Figure 19 B). These results indicate that the weight management composition is effective in improving fatty liver disease.

[0117] To determine whether the weight management composition could improve systemic inflammation levels, inflammatory biomarkers in tissues were evaluated. As shown above, compared with group 8, groups 11, 12, and 14 showed significantly lower expression of TNFα and IL-1β in the liver. Figure 20 A). Therefore, compared with the HFD control group 8, IL1β mRNA expression was lower in white adipose tissue in each of the weight management combination food or exercise groups (groups 9 and 11–13). TNFα mRNA expression was 2.2 to 3.7 times higher in white adipose tissue compared with groups 9 and 11–13. Figure 20 B). These observations of reduced inflammation in white adipose tissue and liver suggest that the weight management composition can effectively reduce systemic inflammation levels.

[0118] These findings clearly demonstrate that the application of weight management compositions treats or improves weight management, mitochondrial capacity, fatty liver disease, dyslipidemia, oxidative stress levels, brown adipose tissue activity, and systemic inflammation levels.

[0119] Example 3: An alternative form of the weight management composition improves body fat oxidation.

[0120] To evaluate some possible ways in which the weight management composition reduces weight or body fat to promote weight management, mice fed with HFD were placed in metabolic cages and given the weight management composition.

[0121] All experiments were approved by the McMaster University Animal Ethics Committee and conducted in accordance with appropriate Canadian guidelines for animal research. Twenty-four C57 / B16 food-induced obese mice were ordered from the Jackson Laboratory and placed on HFDs (Teklad#TD.06414) containing 60% fat energy at 6 weeks of age and fed freely. At approximately 12 weeks of age, the mice were divided into experimental groups, standardized to average body weight, placed in metabolic cages (Columbus Laboratory Animal Monitoring System; Columbus Instruments), and allowed to acclimatize to the new environment for approximately 12 hours. After the acclimatization period, the mice remained on the 60% HFDs used in groups 1 and 8 above for one day to collect metabolic data for each group, while being fed control HFDs before any treatment. After 24 hours of measurement against the control HFD (i.e., at the end of Day 1), mice were fed according to the following group assignments: Group 15 was given the same 60% HFD control as before; Group 16 was given only the weight management combination A diet from Examples 1 and 2; and Group 17 was given the weight management combination C diet from Example 2. As a standard low-fat diet control, a group of eight mice (Group 18) was fed the Chow diet from Examples 1 and 2 throughout the study. Measurements were collected for three days after Day 1 (referred to as Days 1–3) to observe any changes in metabolic activity during the administration of the experimental diets. Lipid oxidation rates were collected by indirect calorimetry and calculated based on the following equation: (1.6946 × VO2) - (1.7012 × VCO2). Activity levels were collected by beam breakage measured on the x-axis of the metabolic cage.

[0122] result

[0123] During day 1, the rate of lipid oxidation was comparable among the three groups controlling HFD. Figure 21 A). It was expected that, due to the low fat content of the food, the lipid oxidation rate in group 18, fed with Chow food, was approximately 65% ​​lower. After a 3-day treatment period, compared to group 15 fed with HFD, the mean lipid oxidation rates in groups 16 and 17, fed with weight management combination foods A and C respectively, were 21% and 29% higher, respectively. Figure 21 B). Activity levels were also measured, and it was shown that activity levels were similar across all four groups during day 1. Figure 21 C). Interestingly, during the 3-day treatment period, the activity levels of groups 16–18 were significantly higher than those of group 15, which was fed HFD (C). Figure 21 (D). While not wishing to be bound by any particular mechanism, these findings suggest that weight management compositions promote weight management in two ways: by increasing the rate of basal fat oxidation to promote fat reduction and by increasing physical activity to more generally promote energy expenditure.

[0124] Together, the findings from this study surprisingly reveal that administering a weight management composition containing weight loss agents and mitochondrial enhancers to individuals or those who exercise regularly is an effective strategy for improving weight management, mitochondrial capacity, fatty liver disease, dyslipidemia, oxidative stress levels, brown adipose tissue activity, and systemic inflammation levels.

[0125] The compositions and methods of this invention advantageously provide individuals with a means to achieve weight loss with or without exercise or dieting. Furthermore, the weight management compositions of this invention have been scientifically validated and allow for individual use without the need to spend time determining which supplements to use and what beneficial effects will be provided. This method and composition also provide individuals in need with health benefits that synergize with the health benefits derived from exercise.

Claims

1. A weight management composition for mammals, said weight management composition comprising: i) Weight loss agents; ii) Mitochondrial enhancers; and iii) One or more physiologically acceptable excipients and / or one or more nutrient sources, or without the additional ingredients in iii). The weight loss agent is composed of 50-1000 mg of green tea extract, 50-1000 mg of green coffee bean extract, and 15-100 mg of trichosamine daily. The mitochondrial enhancer is composed of 50-5000 mg of beetroot extract, 50-900 mg of coenzyme Q10, 50-900 mg of alpha-lipoic acid, and 50-900 mg of vitamin E, or... The weight loss agent is composed of 50-1000 mg of green tea extract, 50-1000 mg of green coffee bean extract, 15 mg-100 mg of trichosamine, 50-500 mg of black tea extract, and 500 mg-3 g of conjugated linoleic acid, at a daily dosage. The mitochondrial enhancer is composed of 50-5000 mg of beetroot extract, 50-900 mg of coenzyme Q10, 50-900 mg of alpha-lipoic acid, 50-900 mg of vitamin E, and 1-5 g of creatine. Furthermore, the amount of each component in the composition is selected such that it results in a reduction of fat mass of at least 1% and roughly maintains lean meat mass in the mammal.

2. The composition according to claim 1, wherein the one or more nutrient sources are selected from: proteins, carbohydrates, lipids, fiber, vitamins and minerals.

3. The composition according to claim 1, wherein the composition is decaffeinated.

4. The composition according to claim 1, wherein the composition is formulated for oral administration.

5. The composition according to claim 1, wherein the composition is provided in two different dosage forms.

6. The composition of claim 1, wherein the weight-loss agent is provided in a first dosage form and the mitochondrial enhancer is provided in a second dosage form.

7. Use of the weight management composition of any one of claims 1 to 6 in the preparation of a medicament for promoting weight management in mammals.

8. A weight management composition for mammals, comprising the following: i) Weight loss agents; ii) Mitochondrial enhancers; and iii) One or more physiologically acceptable excipients and / or one or more nutrient sources, or without the additional ingredients in iii). The weight loss agent is composed of 5-50% by weight each of green tea extract and green coffee bean extract, and 0.05-50% by weight of trichosamine; the mitochondrial enhancer is composed of 1-50% by weight each of beetroot extract, coenzyme Q10, and vitamin E, and 5-50% by weight of alpha-lipoic acid, or... The weight loss agent is composed of 5-50% by weight each of green tea extract and green coffee bean extract, 0.05-50% by weight of trichosamine, 20-70% by weight of conjugated linoleic acid, and 5-50% by weight of black tea extract. The mitochondrial enhancer is composed of 1-50% by weight each of beetroot extract, coenzyme Q10 and vitamin E, 5-50% by weight of alpha-lipoic acid, and 20-70% by weight of creatine. Furthermore, the amount of each component in the composition is selected such that it results in a reduction of fat mass of at least 1% and roughly maintains lean meat mass in the mammal.

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