Medicine for preventing or treating metabolic diseases and application

Abstract

The invention relates to a medicine for preventing or treating metabolic diseases and application thereof, relates to the technical field of biological medicine, and discloses application of N-acetylvaline in preparation of products for treating or preventing metabolic diseases. The invention provides a novel metabolism regulation medicine, functional food or nutritional supplement based on N-acetylvaline, which is applied to prevention and treatment of obesity and metabolic diseases. The N-acetylvaline can maintain energy balance by adjusting energy intake and energy consumption, so as to effectively prevent and treat obesity and related diseases thereof. As a motion-induced metabolite, N-acetylvaline has dual regulation and control mechanisms: on one hand, energy intake is regulated, and on the other hand, energy consumption is promoted, so that lasting metabolic regulation is realized in a physiological environment; n-acetylvaline is long in acting time in vivo, small in side effect and remarkable in fat reducing effect.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to drugs for preventing or treating metabolic diseases and their applications. Background Art

[0002] Metabolic diseases such as obesity and type 2 diabetes have become increasingly serious public health problems worldwide. The root cause is the long-term imbalance between energy intake and expenditure. Traditional treatments include medication, surgical intervention, and lifestyle changes by adjusting diet and exercise habits. Although these methods can relieve symptoms to a certain extent, they generally have problems such as short-term efficacy, significant side effects, and poor patient compliance.

[0003] In recent years, scientific research has revealed the profound role of exercise in regulating metabolic health. Exercise can not only improve muscle and cardiovascular function, but also maintain energy balance by promoting the production of various metabolites. These metabolites are collectively referred to as "exercise factors" or "exerkines", which play an important role in regulating appetite, promoting energy consumption and improving overall metabolic health. In view of this, the present invention provides drugs and applications for preventing or treating metabolic diseases. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a drug and application for preventing or treating metabolic diseases. The purpose is to provide a newly discovered motor factor N-acetylvaline.

[0005] The technical solution of the present invention to solve the above technical problems is as follows:

[0006] In a first aspect, the invention relates to the use of N-acetylvaline in the preparation of products for treating or preventing metabolic diseases.

[0007] Among them, the structure of N-acetyl valine is as follows:

[0008] Furthermore, the metabolic disease includes obesity, diabetes or metabolic syndrome.

[0009] Furthermore, the product includes a medicine, a functional food or a nutritional supplement.

[0010] In a second aspect, a drug for treating or preventing metabolic diseases comprises the N-acetylvaline.

[0011] Furthermore, the medicine also includes pharmaceutical excipients and / or carriers.

[0012] Furthermore, the dosage form of the drug includes at least one of an injection, an oral tablet, an oral capsule, and an oral liquid preparation.

[0013] Furthermore, when the dosage form of the drug is an injection, the drug also includes dimethyl sulfoxide (DMSO), Kolliphore (polysorbate) and normal saline. Dimethyl sulfoxide is used as the main solvent to increase the solubility of N-acetylvaline; polysorbate is used as an adjuvant; and normal saline provides physiological compatibility, so that the complex can be effectively absorbed after injection in vivo.

[0014] Furthermore, the volume ratio of the dimethyl sulfoxide, the polysorbate and the physiological saline is 1:1:8 to form a solvent system.

[0015] The preparation method of the injection is as follows: commercially available N-acetyl valine is dissolved in the above solvent system in proportion; the dissolution process is carried out at room temperature and needs to be gently stirred until it is completely dissolved to obtain a stable solution.

[0016] A third aspect provides a functional food, wherein the active ingredient of the functional food includes the N-acetylvaline.

[0017] A fourth aspect provides a nutritional supplement, wherein the active ingredient of the nutritional supplement includes the N-acetylvaline.

[0018] The present invention newly discovered an N-acetylvaline (NAV) exercise factor; experimental results show that the concentration of N-acetylvaline in the blood increases significantly after exercise, and it can maintain energy balance through a dual mechanism of simultaneously regulating energy intake and consumption; although the specific mechanism of action of N-acetylvaline has not yet been fully elucidated, it is an exercise-induced metabolic regulator and has shown great application potential in the prevention and treatment of metabolic diseases.

[0019] The present invention proposes a novel metabolic regulation drug, functional food or nutritional supplement based on N-acetyl valine, which is applied to the prevention and treatment of obesity and metabolic diseases; N-acetyl valine regulates energy intake and energy consumption, maintains energy balance, and thus effectively prevents and treats obesity and related diseases (such as type 2 diabetes). As an exercise-induced metabolite, N-acetyl valine has a dual regulation mechanism: on the one hand, it regulates energy intake, and on the other hand, it promotes energy consumption, thereby achieving lasting metabolic regulation in a physiological environment; N-acetyl valine has a long action time in the body, has few side effects, and has a significant fat-reducing effect.

[0020] The beneficial effects of the present invention are:

[0021] (1) Long-term and comprehensive energy balance regulation: N-acetylvaline provides a dual-regulation metabolic management method by simultaneously regulating energy intake and energy expenditure. Unlike traditional drugs that only target a single mechanism (such as suppressing appetite or increasing energy expenditure), the present invention achieves a long-lasting and significant weight loss effect through this "dual-effect" mechanism, avoiding the problem of short-term effects of traditional treatments.

[0022] (2) Fewer side effects and better tolerance: The experimental results of the present invention show that N-acetyl valine has fewer side effects and good tolerance, especially at high doses, it still shows good safety; compared with existing obesity treatment drugs (such as hormone drugs, appetite suppressants) that are prone to cause serious side effects (such as cardiovascular disease, mental disorders, etc.), N-acetyl valine has higher physiological compatibility and safety because it exists naturally in the body and is induced by exercise.

[0023] (3) High in vivo absorption rate: The present invention significantly improves the in vivo solubility and bioavailability of N-acetylvaline by adopting a 1:1:8 DMSO:Kolliphore:normal saline solvent system; this solvent combination effectively optimizes the in vivo stability of N-acetylvaline, allowing it to maintain a high concentration level in the blood for a long time, thereby prolonging the duration of its metabolic regulation effect.

[0024] (4) Applicable to different types of metabolic diseases: The present invention is not only applicable to the treatment of obesity, but can also be applied to the prevention and treatment of related diseases such as type 2 diabetes and metabolic syndrome; experimental data show that N-acetylvaline can effectively improve glucose tolerance and reduce body weight, and has broad clinical application potential. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The structure of N-acetylvaline (NAV) of the present invention and its characteristic responsiveness to exercise intensity; wherein A is the intersection of the top 20 most significant metabolites in serum non-targeted metabolomics of MICT and HIIT in three different forms of exercise; B is a schematic diagram of the structure of N-acetylvaline;

[0026] Figure 2 The figure is a dynamic change diagram of the relative concentration of N-acetylvaline in human exercise serum of the present invention; wherein AC is the non-targeted metabolomics temporal characteristics of N-acetylvaline to different forms and intensities of exercise; all data are expressed as Mean±Sd, and the P value between each group is calculated using a two-factor repeated measures analysis of variance, and the correlation between NAV and lactate is calculated using a Pearson correlation analysis;

[0027] Figure 3 is a correlation diagram of N-acetylvaline and lactic acid of the present invention;

[0028] Figure 4 The absolute concentration change diagram of N-acetylvaline in the serum of animals and humans after exercise of the present invention; wherein A is the absolute quantitative analysis of serum N-acetylvaline in mice after a single exhaustive exercise; B is the absolute quantitative analysis of serum N-acetylvaline after different forms of HIIT exercise; all data are expressed as Mean±Sd, and two-way ANOVA is used for Figure A, and paired sample T test is used to calculate the P value between groups for Figure B;

[0029] Figure 5 This is a correlation analysis diagram of N-acetylvaline of the present invention on obesity, type 2 diabetes, high BMI risk and physical activity level; wherein A is obesity; B is type 2 diabetes; C is high BMI risk; and D is physical activity level;

[0030] Figure 6 The acute effects of different concentrations of N-acetylvaline on the food intake, water intake and body weight of lean mice of the present invention are shown in Figure 1; wherein A is the effect of acute injection of different concentrations of N-acetylvaline on the food intake and water intake of lean mice; B is the acute weight change of mice after injection of different concentrations of N-acetylvaline; all data are expressed as Mean±Sd; and the P value is calculated using the independent sample t test;

[0031] Figure 7 The figure is a graph showing the acute effects of N-acetylvaline of the present invention on the food intake, water intake and body weight of diet-induced obese mice; wherein A is the effect of different concentrations of N-acetylvaline on the food intake and water intake of obese mice; B is the acute weight change of DIO mice after injection of different concentrations of N-acetylvaline; all data are expressed as Mean±Sd; and the P value is calculated using the independent sample t test;

[0032] Figure 8 The pharmacokinetic diagram of N-acetylvaline of the present invention in lean mice and obese mice;

[0033] Fig. 9 The figure is a graph showing the acute effect of N-acetylvaline of the present invention on the energy metabolism parameters of lean mice; wherein, AF are the effects of 100 mg / kg dose of N-acetylvaline injection on the food intake, energy consumption, activity level, and energy metabolism parameters (oxygen uptake, carbon dioxide production, respiratory quotient) of lean mice, respectively. The gray part in the figure represents the night cycle; all data are expressed as Mean±Sd. Two-way repeated measures ANOVA was used to calculate the P value between groups;

[0034] Fig.10: This is a graph showing the acute effect of N-acetylvaline of the present invention on energy metabolism parameters of obese mice; wherein AF are the effects of 100 mg / kg dose of NAV injection on food intake, energy consumption, activity and energy metabolism parameters (oxygen uptake, carbon dioxide production, respiratory quotient) of obese mice, respectively. The gray part in the figure represents the night cycle; all data are expressed as Mean±Sd; two-way repeated measures analysis of variance was used to calculate the P value between groups;

[0035] Fig.11 The figure is the effect of a single injection of N-acetylvaline on the food intake and body weight changes of obese mice in one week; wherein all data are expressed as Mean±Sd, and the P value is calculated using the independent sample t test for Figures A and D, and the two-factor repeated measures analysis of variance for Figures B and C;

[0036] Fig.12 The figure is a long-term effect of N-acetylvaline on the body weight and food intake of obese mice; wherein A is a representative picture of the effect of continuous injection of N-acetylvaline (10 days) on the body weight of DIO mice; BC is the effect of continuous N-acetylvaline intervention (10 days) on the food intake and body weight changes of obese mice; all data are expressed as Mean±Sd, and P values ​​are calculated using two-way repeated measures ANOVA;

[0037] Fig.13 The figure is the effect of N-acetyl valine of the present invention on fat weight, body composition and tissue weight of obese mice; wherein A is a representative picture of the effect of continuous N-acetyl valine intervention on brown fat and white fat tissue of mice; B is a representative picture of the effect of continuous N-acetyl valine intervention on body composition of mice; C is the effect of N-acetyl valine intervention on fat and tissue weight of obese mice; D is the effect of N-acetyl valine intervention on body fat percentage of obese mice; all data are expressed as Mean±Sd, and P values ​​are calculated using independent sample t-test;

[0038] Fig.14 The figure is a long-term effect diagram of N-acetylvaline of the present invention on glucose tolerance, fasting blood glucose and energy metabolism parameters of obese mice; wherein, AE is the effect of continuous N-acetylvaline intervention on fasting blood glucose and energy metabolism parameters (oxygen uptake, carbon dioxide production, respiratory quotient, activity) of obese mice; all data are expressed as Mean±Sd, and P values ​​are calculated using independent sample t-test. DETAILED DESCRIPTION

[0039] The principles and features of the present invention are described below, and the examples are only used to explain the present invention and are not used to limit the scope of the present invention. If no specific technology or conditions are specified in the embodiments, the technology or conditions described in the literature in this field or the product instructions are used. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased through regular channels.

[0040] Example 1

[0041] 1. Response of N-acetylvaline to acute exercise and its physiological relevance.

[0042] 1.1 Experimental reagents and materials.

[0043] (1) Experimental reagents: acetonitrile (Honeywell, AH015-4), methanol (Honeywell, AH230-4), N-acetylvaline standard (MedChemExpress, HY-W015466), N15-acetylvaline standard (CIL, 355808-21-8), Kolliphor EL (Sigma, C5135-500G), dimethyl sulfoxide (Sigma, D8418-50ML), formic acid (Honeywell, 64-18-6), pure water, and normal saline;

[0044] (2) Experimental instruments: Agilent 1290 Infinity II ultra-high performance liquid chromatography system, Waters ACQUITY HSS-T3 column (3.0×100 mm, 1.8 μm), Waters ACQUITY BEH Amide column (2.1×100 mm, 1.7 μm), 5600 Triple TOF Plus (AB Sciex, equipped with an electron spray ionization source), Shimadzu LC-MS8050 system (for targeted metabolomics analysis), Shim-pack GIST C18-AQ HP column (3 μm, 2.1×100 mm), and low-temperature high-speed centrifuge.

[0045] 1.2 Experimental methods

[0046] 1.2.1 Human subjects and groups.

[0047] Human subjects: This experiment was approved by the Sports Science Research Ethics Committee of Beijing Sport University (2022188H). The subjects of this study cohort were healthy adults (n = 100), and all participants were randomly assigned to three main exercise groups: swimming, running, and cycling, each of which was further divided into moderate-intensity training (MICT) and high-intensity interval training (HIIT). Each main exercise group consisted of swimming (n = 40, of which MICT n = 20 and HIIT n = 20), running (n = 40, MICT n = 20, HIIT n = 20), and cycling (n = 20, MICT n = 10, HIIT n = 10). Inclusion criteria included healthy adults aged between 18 and 35 years, without regular exercise habits, and willing to participate and understand the content of the study and sign informed consent. Exclusion criteria included individuals with cardiovascular disease, metabolic disease, or other chronic health problems, individuals who had participated in other clinical studies in the past six months, and individuals with a history of drug allergy or known allergy to any substance used in the study. All subjects signed an informed consent form before participating in the experiment, confirming that they understood and agreed to the purpose, process and potential risks of the experiment.

[0048] 1.2.2 Experimental animals and groups.

[0049] Experimental animals and grouping: This experimental protocol has been approved by the Sports Science Ethics Committee of Beijing Sport University. The experiment used 8-12 week old C57BL6J mice (n=24), which were obtained from Vital River Company. The experiment was divided into two groups: pre-exercise group (n=6) and exhaustive exercise group (n=18). The exhaustive exercise group was further subdivided into three time points: 0 min (n=6), 15 min (n=6) and 30 min (n=6) after exercise. At these specific time points, blood samples of mice were collected by eye bleeding for subsequent biochemical analysis.

[0050] 1.2.3 Collection of human and animal blood samples.

[0051] Human and Animal Blood Sample Collection: In this experiment, set time points were used to collect blood samples from human subjects and animals. Specific time points include before exercise and 0 minutes, 15 minutes, and 30 minutes after exercise for human subjects; for animals, samples were collected at 0 minutes, 15 minutes, and 30 minutes after exercise. During the collection step, first ensure that all tools and containers are sterile. Human subjects draw blood from the forearm vein, and animals draw blood from the retro-ocular vein. The blood is immediately placed in a test tube containing anticoagulant and gently shaken to mix. After that, the sample is centrifuged at 3000 rpm for 10 minutes at room temperature to allow the plasma to be layered on the top of the test tube. It is then extracted with a pipette and transferred to a new sterile test tube for cryopreservation or biochemical analysis as needed.

[0052] 1.2.4 Serum non-targeted metabolomics testing.

[0053] Serum non-targeted metabolomics testing: Non-targeted metabolomics studies were performed at LipidALL Technologies, Changzhou, China. Metabolites were extracted from 50 μL of serum by adding 200 μL of ice-cold methanol containing 0.28 mM phenylhydrazine. Chromatographic separation was performed using an ultra-high performance liquid chromatography system (Agilent 1290 Infinity II; Agilent Technologies). For reversed-phase chromatography, polar metabolites were separated on a Waters ACQUITY HSS-T3 column (3.0 × 100 mm, 1.8 μm), while hydrophilic interaction liquid chromatography used a Waters ACQUITY BEH Amide column (2.1 × 100 mm, 1.7 μm). Mass spectrometry analysis was performed using a high-resolution mass spectrometer (5600 TripleTOF Plus, AB Sciex) equipped with an electron spray ionization source. MS / MS analysis of metabolites was performed using information-dependent acquisition mode with a collision energy set to (-) 35 ± 15 eV. Data processing was performed using MarkerView (version 1.3, AB Sciex) and PeakView (version 2.2, ABSciex) software. Metabolite identification was performed by comparison with standard references in the HMDB (https: / / hmdb.ca) and METLIN (https: / / metlin.scripps.edu) databases.

[0054] 1.2.5 Absolute quantification of N-acetylvaline.

[0055] Absolute quantification of N-acetylvaline: Targeted metabolomics analysis was performed using a Shimadzu LC-MS8050 system in negative ion mode by electrospray ionization (ESI) mass spectrometry. The operating parameters were set as follows: the gas temperature of the ESI source was 250°C, the gas flow was 12 L / min, the nebulizer pressure was 25 psi, the sheath gas temperature was set to 300°C, the sheath gas flow was also 12 L / min, and the capillary voltage was 3500 V. Chromatographic separation was performed using a Shimadzu Shim-pack GIST C18-AQ HP column (3 μm, 2.1 × 100 mm), the mobile phase A was 95% water, 5% acetonitrile and 0.1% formic acid, and the mobile phase B was 100% acetonitrile. The initial flow rate was set to 0.2 mL / min, and the mobile phase ratio was gradually adjusted from 60% A: 40% B to 90% B: 10% A. Under these conditions, the peak time of N-acetylvaline was 0.95 minutes. The quantitative analysis used the internal standard method, with N-acetylvaline labeled with N15 as the internal standard. The concentration of endogenous metabolites was calculated by preparing a standard curve containing the target metabolite and the internal standard. All samples were analyzed using a unified triple quadrupole mass spectrometry method, including the same instrument settings and operating procedures, to ensure the consistency and accuracy of the experimental results. In addition, the dilution effect of plasma in sample preparation was also taken into account during the quantitative process to improve the accuracy of the data.

[0056] 1.2.6 Mendelian randomization analysis.

[0057] Mendelian randomization analysis: To explore the causal relationship between N-acetylvaline (NAV) and the risk of metabolic diseases, this paper used Mendelian randomization analysis. This analysis uses genetic variation as an instrumental variable to assess the causal relationship between exposure factors (here, NAV levels) and outcomes (such as BMI, obesity, and risk of type 2 diabetes). The data used in this paper comes from the METSIM study, a single-site cohort study covering 10,197 men aged 45 to 74 in Kuopio, Finland, focusing on the risk factors of type 2 diabetes and cardiovascular disease. By performing non-targeted metabolomics analysis on EDTA plasma samples of 6,136 non-diabetic men in the METSIM database, this paper identified the association of multiple metabolites with genetic variations. After performing single-variant genome-wide association analysis (GWAS) of 1,391 metabolites, a total of 2,030 independent genetic loci associated with metabolite levels were identified.

[0058] 1.3 Experimental results

[0059] like Figure 1As shown in the figure, after various forms of human exercise such as swimming, running and cycling, non-targeted serum metabolomics analysis revealed that metabolites closely related to exercise, such as L-Lactic acid, Pyruvate, Oxoglutaric acid, L-Phenylalanine, L-Malic acid, N-Acetylvaline, 2-Ketobutyric acid, Fumaric acid, Pantothenic acid, Xanthosine, and N-lactoyl-Phenylalanine, all showed high significance levels ( Figure 1 N-acetyl valine ( Figure 1 B) is one of the most significant metabolites in the comparison between high-intensity and moderate-intensity exercise in all forms ( Figure 2 A to C), and had a very high correlation level with the known intensity-dependent metabolite lactate ( Figure 3 ). These results support that N-acetylvaline may be a potential exercise-induced metabolite.

[0060] Through targeted NAV precise measurement, it was confirmed that N-acetyl valine was significantly increased after all types of high-intensity exercise ( Figure 4 In the mouse exhaustive exercise model, serum concentrations of N-acetylvaline increased 4-fold ( Figure 4 These results confirm that N-acetylvaline is a characteristic factor induced by high-intensity exercise.

[0061] Two-sample Mendelian randomization analysis using the METSIM database showed that high levels of circulating NAV were directly causally associated with lower BMI and may reduce the risk of obesity (OB) and type 2 diabetes (T2DM). In addition, plasma NAV levels were negatively correlated with physical activity levels, suggesting that NAV may play a role in regulating energy balance in the body ( Figure 5 (A to D).

[0062] Example 2

[0063] 1. Effect of N-acetylvaline intervention on the metabolic health of mice.

[0064] 1.1 Experimental reagents and materials.

[0065] (1) Experimental reagents: N-acetylvaline, saline, DMSO, Kolliphore, isoflurane;

[0066] (2) Experimental instruments: high-precision electronic balance, metabolic cage;

[0067] (3) Experimental animals: 20-week-old C57BL6 / J mice (Viton Life Sciences).

[0068] 1.2 Experimental methods

[0069] 1.2.1 Animal grouping.

[0070] Animal grouping: Male C57BL6 / J mice were purchased from Weitonglihua Biotechnology Co., Ltd., 6 weeks old, 24 mice. The mice were randomly divided into a normal diet group and a high-fat diet group. Each category of mice was further randomly assigned to an N-acetylvaline intervention group (NAV) and a corresponding solvent control group (Veh). That is, lean mice were divided into a NAV intervention group (NAV-WT) and a solvent control group (Veh-WT), and obese mice were also divided into a NAV intervention group (NAV-DIO) and a solvent control group (Veh-DIO).

[0071] 1.2.2 Diet-induced obesity model.

[0072] Diet-induced obesity model: This study established a diet-induced obesity model by providing a high-fat diet supplied by Keao Xieli. Starting from 6 weeks of age, C57BL / 6J mice were fed a diet containing 60% of energy from fat for 12 weeks to promote the development of obesity and its related metabolic abnormalities. The standard for obese mice modeling is that the weight of mice fed a high-fat diet exceeds the weight of mice in the same litter that eat a normal diet by more than 30%.

[0073] 1.2.3N-acetylvaline intervention plan.

[0074] N-acetylvaline intervention protocol: This experiment performed acute and long-term intervention of N-acetylvaline by intraperitoneal injection of mice. N-acetylvaline was dissolved in a solvent of DMSO, Kolliphore and saline at a ratio of 1:1:8. In the acute intervention, mice received a single injection of 25 mg / kg, 50 mg / kg and 100 mg / kg, respectively, and the control group was injected with an equal volume of solvent solution. The food intake, water intake and body weight changes of the mice were recorded within 12 hours and 24 hours after injection. In the long-term intervention protocol, all mice were intraperitoneally injected with N-acetylvaline at a dose of 100 mg / kg / day for 10 days. The control group mice were injected with the same volume of solvent solution. During this period, the indicators tested included fasting blood glucose, glucose tolerance, insulin tolerance, food intake, body weight, tissue weight, body fat percentage, oxygen uptake, carbon dioxide production and activity. Various indicators were recorded regularly during the experiment, and the results of each group were analyzed and compared at the end of the experiment.

[0075] 1.2.4 Metabolic cage analysis of acute food intake and energy metabolism parameters of mice.

[0076] Metabolic cage analysis of acute food intake and energy metabolism parameters of mice: In this study, the present invention uses the SablePromethion system (model PROMETHION BZ1) to measure the acute food intake and energy metabolism parameters of mice. First, the system is calibrated and the required parameters are set, including oxygen consumption, carbon dioxide production, food intake, water intake and animal activity. The mice are adapted to the system for 24 hours before measurement, and then placed alone in a metabolic cage equipped with food and water for continuous 24 hours of monitoring. The system automatically records the weight of food and water at the beginning and end of the experiment. At the same time, by analyzing the changes in gas composition in the cage, the energy consumption and respiratory exchange ratio of the mice are continuously calculated. After the experiment, the software included with the system is used to process the data, and detailed parameters such as food intake, water intake, energy consumption, respiratory quotient and activity are output, and further data standardization and statistical analysis are performed.

[0077] 1.2.5 Glucose tolerance and insulin tolerance test.

[0078] Glucose tolerance and insulin tolerance test: For the glucose tolerance test, mice fasted for 6 hours from 7 am (allowed free access to water), and then injected with 2g / kg body weight of glucose by intraperitoneal injection. Blood glucose levels were measured at 0, 20, 40, 60 and 120 minutes by blood sampling from the tail and using a glucometer. For the insulin tolerance test, mice fasted for 6 hours from 7 am (allowed free access to water), and then injected with 0.75U / kg body weight of insulin dissolved in saline by intraperitoneal injection. Blood glucose levels were measured at 0, 20, 40, 60 and 120 minutes by blood sampling from the tail and using a glucometer. The data of the glucose tolerance test and the insulin tolerance test were recorded by the blood glucose levels at each time point, and the area under the blood glucose curve (AUC) was calculated. The differences between the groups were compared using one-way analysis of variance (ANOVA) to evaluate the glucose tolerance and insulin sensitivity of mice.

[0079] 1.2.6 Dual-energy X-ray absorptiometry (DEXA) was used to measure the body composition of mice.

[0080] Dual-energy X-ray absorptiometry (DEXA) measurement of mouse body composition: After fasting for 4 hours (free access to water), the mice were subjected to body composition measurement using a DEXA bone densitometer (LunarIDXA GE Healthcare). The mice were anesthetized with mild isoflurane before the test to reduce movement interference. The total body fat content, lean body mass, and total body fat percentage of the mice were obtained by DEXA scanning.

[0081] 1.3 Experimental results

[0082] The experimental results are as follows Figures 6 to 14 As shown in the figure, it can be seen that: (1) after acute NAV injection (doses of 25 mg / kg, 50 mg / kg, and 100 mg / kg) in wild-type (WT) mice, no significant effects were observed on the food intake, water intake, body weight, and energy metabolism parameters of the mice at these doses ( Figure 6 (A to B in the figure). (2) In the DIO mouse model, which simulates metabolic abnormalities, NAV injection at a dose of 50 mg / kg significantly reduced food intake within 12 hours; while a dose of 100 mg / kg led to a significant decrease in food intake and body weight for 4 consecutive days. In addition, NAV injection at a dose of 100 mg / kg also reduced CO2 production and respiratory quotient in DIO mice, indicating that NAV may have altered the energy metabolism pattern of DIO mice ( Figure 7 From A to B, Figure 8 , Fig. 9 A to F, Fig.10 (A to F). (3) In a 10-day NAV intervention experiment using a diet-induced obese (DIO) mouse model, the NAV-treated group showed a significant decrease in food intake, body weight, body fat percentage, and white adipose tissue weight, and a significant improvement in glucose tolerance compared with the control group, while the sizes of other organs remained unchanged ( Fig.11 A to D, Fig.12 A to D, Fig.13 A to D, Fig.14 Figure 5 (A to E). These results suggest that NAV improves adiposity and glucose homeostasis by reducing energy intake.

[0083] In summary, the N-acetyl valine of the present invention is a characteristic metabolite induced by exercise, which has a dual effect on the energy balance regulation of obese patients from the two aspects of energy intake and energy expenditure, reduces the weight of obese patients and improves glucose tolerance. The substance has a long action time in the body, has few side effects, and has a significant fat-reducing effect.

[0084] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. Application of N-acetylvaline in the preparation of products for treating or preventing metabolic diseases.

2. The use according to claim 1, characterized in that: The metabolic disease includes obesity, diabetes or metabolic syndrome.

3. The use according to claim 1, characterized in that: The products include pharmaceuticals, functional foods or nutritional supplements.

4. A drug for treating or preventing metabolic diseases, characterized in that: The drug comprises the N-acetylvaline according to any one of claims 1 to 3.

5. A drug for treating or preventing metabolic diseases according to claim 4, characterized in that: The medicine also includes pharmaceutically acceptable adjuvants and / or carriers.

6. A drug for treating or preventing metabolic diseases according to claim 4, characterized in that: The dosage form of the drug includes at least one of an injection, an oral tablet, an oral capsule, and an oral liquid preparation.

7. A drug for treating or preventing metabolic diseases according to claim 6, characterized in that: When the dosage form of the drug is an injection, the drug further comprises dimethyl sulfoxide, polysorbate and physiological saline.

8. A drug for treating or preventing metabolic diseases according to claim 7, characterized in that: The volume ratio of the dimethyl sulfoxide, the polysorbate and the physiological saline is 1:1:

8.

9. A functional food, characterized in that: The active ingredient of the functional food comprises the N-acetylvaline according to any one of claims 1 to 3.

10. A nutritional supplement, characterized in that: The active ingredient of the nutritional supplement comprises the N-acetyl valine according to any one of claims 1 to 3.

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