Application of γ-aminobutyric acid (GABA) in the preparation of drugs to prevent and treat adverse reactions induced by olanzapine

Abstract

This invention discloses the application of γ-aminobutyric acid (GABA) in the preparation of drugs for preventing and treating olanzapine-induced adverse reactions. The invention discovers that GABA can inhibit macrophage infiltration in subcutaneous fat and suppress the polarization of pro-inflammatory M1 macrophages, thereby inhibiting inflammation in adipose tissue and improving olanzapine-induced insulin resistance. Furthermore, it finds that GABA can prevent and treat olanzapine-induced lipid metabolism abnormalities by improving adipogenesis and ectopic deposition. This invention provides an important theoretical basis for the use of GABA in preventing and treating olanzapine-induced adverse reactions and offers a new approach to the preparation of drugs for preventing and treating olanzapine-induced adverse reactions.

Description

Technical Field

[0001] This invention relates to the field of drugs for preventing and treating adverse reactions induced by olanzapine, specifically to the application of γ-aminobutyric acid (GABA) in the preparation of drugs for preventing and treating adverse reactions induced by olanzapine. Background Technology

[0002] Olanzapine (OLZ) is a second-generation antipsychotic drug and has become a first-line treatment in clinical practice. Compared to first-generation antipsychotics, it has fewer extrapyramidal side effects, but it can cause more serious endocrine and metabolic abnormalities, such as hyperglycemia, hyperlipidemia, hypercholesterolemia, and weight gain. The common pathological basis for these abnormalities is insulin resistance. Schizophrenia patients often require long-term medication, and this adverse effect of olanzapine not only reduces medication adherence but also significantly increases the risk of type 2 diabetes and cardiovascular disease, becoming one of the important factors limiting the clinical application of olanzapine. Therefore, addressing the clinical problem of insulin resistance induced by olanzapine is of great significance.

[0003] The development of insulin resistance is closely related to the inflammatory response in adipose tissue. Besides being an important secretory organ, adipose tissue also plays a crucial role in immune regulation, containing various immune cells. Among these, macrophages are the most abundant cell type besides adipocytes, playing a vital role in regulating adipose tissue metabolism and inflammatory responses, and are closely associated with obesity-related chronic inflammation and insulin resistance. Macrophages exist primarily in adipose tissue in two subsets, activated by two different pathways and exhibiting different immune states. Classically activated M1 macrophages primarily exhibit a pro-inflammatory state, secreting pro-inflammatory factors; while selectively activated M2 macrophages exhibit an anti-inflammatory state, secreting anti-inflammatory factors. In the adipose tissue of obese individuals, macrophage polarization into the M1 type is a significant cause of adipose tissue inflammation and a crucial pathological factor further inducing insulin resistance.

[0004] As a small molecule metabolite, gamma-aminobutyric acid (GABA) is best known for its role as a major inhibitory neurotransmitter, regulating communication between neurons. However, its functions and mechanisms of action outside the central nervous system are less well-studied. Recent studies have revealed that GABA is also present in various tissues and organs outside the brain, including the intestines, liver, and pancreas, and plays important physiological roles beyond its neurotransmitter function. One of its key functions is participation in immune regulation, which plays a crucial role in glucose and lipid metabolism. So, does GABA affect glucose and lipid metabolism through its participation in immune regulation? Recent research shows that in obese individuals, subcutaneous adipose tissue is less prone to inflammation compared to visceral fat because macrophage infiltration and M1 polarization are suppressed. The mechanism by which subcutaneous adipose tissue maintains this immune characteristic is the activation of GABA signaling. This study reveals the important physiological role of GABA in maintaining adipose tissue metabolic homeostasis by regulating macrophage immune function.

[0005] GABA levels in brain tissue are associated with severe mental illnesses, including schizophrenia, bipolar disorder, and major depressive disorder, and its role is to regulate the excitability of neurons. The GABA hypothesis in schizophrenia suggests that GABA is effective not only for the positive symptoms of schizophrenia but also for the negative symptoms and cognitive impairment caused by prefrontal cortex dysfunction. However, there is currently limited research on the role of peripheral GABA. In our research on the effects of olanzapine on neurotransmitters, we unexpectedly discovered that olanzapine can reduce peripheral blood GABA levels (RSC Advances. 2020, 10(31): 18305-18314). This finding attracted our attention, and we conducted an in-depth investigation into the causal relationship and molecular mechanism of olanzapine's reduction of peripheral GABA levels and its induction of metabolic disorders-related side effects. Summary of the Invention

[0006] One object of the present invention is to solve at least the above-mentioned problems and / or defects, and to provide at least the advantages described below.

[0007] Another objective of this invention is to provide the application of γ-aminobutyric acid (GABA) in the preparation of drugs for preventing and treating olanzapine-induced adverse reactions. This invention discovers that GABA can inhibit macrophage infiltration in subcutaneous fat and suppress the polarization of pro-inflammatory M1 macrophages, thereby inhibiting inflammation in adipose tissue and improving olanzapine-induced insulin resistance. It prevents and treats olanzapine-induced lipid metabolism abnormalities by improving lipogenesis and ectopic deposition. This invention provides an important theoretical basis for the use of GABA in preventing and treating olanzapine-induced adverse reactions and offers a new approach to the preparation of drugs for preventing and treating olanzapine-induced adverse reactions.

[0008] To achieve these objectives and other advantages according to the present invention, the use of γ-aminobutyric acid (GABA) in the preparation of drugs for preventing and treating adverse reactions induced by olanzapine is provided.

[0009] Preferably, the adverse reactions induced by olanzapine are insulin resistance and lipid metabolism disorders.

[0010] Preferably, γ-aminobutyric acid (GABA) is an active ingredient in a single-component drug or a combination drug.

[0011] Preferably, insulin resistance includes elevated serum insulin levels, impaired glucose tolerance, and decreased insulin sensitivity caused by adverse reactions to olanzapine.

[0012] Preferably, the lipid metabolism disorder includes fat hyperplasia and ectopic fat deposition in the viscera, brown fat, and liver.

[0013] Preferably, the effective dose of γ-aminobutyric acid (GABA) is 50 mg / kg / d.

[0014] Preferably, GABA refers to a small molecule metabolite of amino acids.

[0015] Preferably, γ-aminobutyric acid (GABA) inhibits olanzapine-induced insulin resistance by suppressing macrophage infiltration in subcutaneous fat, inhibiting the polarization of pro-inflammatory M1 macrophages, and thus suppressing inflammation in adipose tissue.

[0016] Preferably, γ-aminobutyric acid (GABA) helps prevent olanzapine-induced lipid metabolism disorders by improving lipogenesis and ectopic deposition.

[0017] The present invention has at least the following beneficial effects:

[0018] Gamma-aminobutyric acid (GABA) can inhibit macrophage infiltration in subcutaneous fat and suppress the polarization of pro-inflammatory M1 macrophages, thereby inhibiting inflammation in adipose tissue and improving olanzapine-induced insulin resistance. GABA can also improve lipogenesis and ectopic deposition to prevent olanzapine-induced lipid metabolism abnormalities. This provides an important theoretical basis for the use of GABA in preventing and treating olanzapine-induced adverse reactions and offers a new approach for the preparation of drugs to prevent and treat olanzapine-induced adverse reactions.

[0019] Other advantages, objectives and features of the present invention will become apparent in part from the following description, and in part from those skilled in the art through study and practice of the invention. Attached Figure Description

[0020] Figure 1 This is a graph showing the effects of GABA on olanzapine-induced weight gain and insulin resistance in a mouse model of long-term olanzapine exposure, as described in this embodiment of the invention. (A) Mouse body weight, ***P<0.001; (B) Intraperitoneal glucose tolerance test (IPGTT), *P<0.05; (C) Insulin tolerance test (ITT), **P<0.01, ***P<0.001; (D) Mouse serum insulin level, *P<0.05; (E) Insulin resistance index (HOMA-IR), **P<0.01, ***P<0.001.

[0021] Figure 2 This is a diagram showing macrophage infiltration in subcutaneous adipose tissue (sWAT) of a mouse model with GABA-inhibited olanzapine long-term exposure, as illustrated in this embodiment of the invention. (A) is a flow cytometry illustration, showing CD11b... + F4 / 80 + The cells are macrophages, including CD11c. + The cells are M1 macrophages, CD301 + (A) The number of macrophages in the subcutaneous adipose tissue, ***P<0.001; (B) The number of macrophages in the subcutaneous adipose tissue, ***P<0.001; (C) The number of macrophages in the subcutaneous adipose tissue, ***P<0.001; (D) The ratio of M1 to M2 macrophages in the subcutaneous adipose tissue, **P<0.01.

[0022] Figure 3 The diagram shows that GABA did not significantly inhibit macrophage infiltration in the visceral adipose tissue (pWAT) of a mouse model with long-term olanzapine exposure in this invention. (A) is a flow cytometry illustration of CD11b. + F4 / 80 + The cells are macrophages, including CD11c. + The cells are M1 macrophages, CD301 +(A) The cells were M2 macrophages; (B) The total number of macrophages in visceral adipose tissue, ***P<0.001, ns P>0.05; (C) Number of M1 macrophages in subcutaneous adipose tissue, *P<0.05, ns P>0.05; (DE) The ratio of M1 and M2 macrophages in subcutaneous adipose tissue. ns P>0.05.

[0023] Figure 4 This image shows the migration of THP-1 monocytes in adipose tissue-derived conditioned medium in a mouse model of long-term olanzapine exposure to GABA, as described in this embodiment of the invention. (A) Migration of THP-1 in conditioned medium derived from mouse subcutaneous adipose tissue, *P<0.05, **P<0.01; (B) Migration of THP-1 in conditioned medium derived from mouse visceral adipose tissue, *P<0.05. ns P>0.05.

[0024] Figure 5 This image shows the effects of GABA on subcutaneous fat hyperplasia and ectopic fat deposition in a mouse model of long-term olanzapine exposure, as described in this invention. (A) shows the appearance of subcutaneous and visceral adipose tissue in mice; (BC) shows the weight of subcutaneous and visceral fat in mice. **P<0.01, ***P<0.001. ns P>0.05; (D) HE staining of mouse subcutaneous adipose tissue, visceral adipose tissue, brown adipose tissue (BAT) and liver. Detailed Implementation

[0025] The present invention will now be described in further detail with reference to the accompanying drawings, so that those skilled in the art can implement it based on the description.

[0026] It should be understood that terms such as “having,” “comprising,” and “including” as used herein do not imply the presence or addition of one or more other elements or combinations thereof.

[0027] It should be noted that, unless otherwise specified, the experimental methods described in the following implementation plan are all conventional methods, and the reagents and materials described are all commercially available unless otherwise specified.

[0028] GABA is an amino acid metabolite synthesized in vivo from glutamate via glutamate decarboxylase, and can be further metabolized into succinate. GABA is well-known as an inhibitory neurotransmitter, but its other peripheral functions remain unclear. The application of GABA in the preparation of drugs to prevent and treat olanzapine-induced insulin resistance and lipid metabolism disorders has not been reported. We unexpectedly discovered that olanzapine can reduce peripheral blood GABA levels (RSC Advances. 2020, 10(31): 18305-18314), a finding that piqued our interest, prompting us to investigate the causal relationship and molecular mechanism of olanzapine's reduction of peripheral GABA levels and its induction of metabolic disorders.

[0029] <Example 1>

[0030] Supplementing with exogenous GABA can reduce weight gain and pancreatic dysfunction caused by long-term olanzapine exposure.

[0031] Experimental methods:

[0032] Four-week-old female C57BL / 6J mice were randomly divided into three groups of 10 mice each using a random number table. After two weeks of acclimatization, the control group (Saline), the olanzapine group (OLZ), and the GABA treatment group (OLZ+GABA) were fed a customized diet (31 kcal% fat, 55 kcal% carbohydrate, 14 kcal% protein, MolDiets). Mice in the control group received saline via gavage from week 0 to 10, and simultaneously received saline via intraperitoneal injection from week 5 to 10. Mice in the olanzapine group received OLZ via gavage (3 mg / kg / day) from week 0 to 10, and simultaneously received saline via intraperitoneal injection from week 5 to 10. Mice in the GABA treatment group received OLZ via gavage (3 mg / kg / day) from week 0 to 10, and simultaneously received GABA via intraperitoneal injection from week 5 to 10. Mouse body weight was measured weekly, and blood glucose levels were measured every four weeks. Glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed in week 11.

[0033] (1) Weight and blood glucose monitoring: During the experiment, the living conditions of the mice were observed and recorded daily, including coat color, mental state, activity level, and food and water intake. The weight was measured once a week, and random blood glucose and fasting blood glucose were measured once every 4 weeks.

[0034] (2) GTT test: Mice were fasted for 6 hours and then injected intraperitoneally with glucose (1.5 g / kg). Blood glucose levels were measured by tail tip blood samples at 0, 15, 30, 60, 90 and 120 minutes after glucose administration, and glucose tolerance curves were plotted. The mice were fed again after the experiment.

[0035] (3) ITT test: Mice were fasted for 2 hours and then injected subcutaneously with insulin (1.0 U / kg) in the back of the neck. Blood glucose levels were measured by collecting blood from the tail tip at 0, 15, 30, 60, 90 and 120 min after insulin administration. Insulin tolerance curves were plotted.

[0036] (4) Serum insulin level detection: Mice were fasted for 6 hours in week 11, then anesthetized and sacrificed. Blood was collected after removing the eyeballs, centrifuged, and the mouse serum was collected. Insulin levels were detected using the ELISA method (Mercodia mouse insulin ELISAkit).

[0037] (5) Calculation of insulin resistance index HOMA-IR: Based on the above fasting insulin level and fasting blood glucose results, the insulin resistance index is calculated according to the formula HOMA-IR = fasting blood glucose x fasting insulin / 22.5.

[0038] Experimental results:

[0039] Analysis of mouse body weight revealed that, compared with the control group, mice in the olanzapine group had a significantly increased body weight, while mice in the GABA-treated group had a significantly decreased body weight compared with the olanzapine group. Figure 1 A). The glucose tolerance test (GTT) revealed that, compared with the control group, mice treated with olanzapine had an increased area under the GTT curve, indicating impaired glucose tolerance, while the GABA-treated group had a decreased area under the GTT curve, indicating improved glucose tolerance. Figure 1 B). Further insulin resistance testing (ITT) revealed that, compared to the control group, olanzapine-treated mice had an increased area under the ITT curve, indicating impaired insulin sensitivity, while the GABA-treated group had a decreased area under the ITT curve, suggesting improved insulin sensitivity. Figure 1 C). Simultaneously, fasting serum insulin levels in mice were measured and the insulin resistance index was calculated. We found that, compared with the control group, mice in the olanzapine group exhibited high serum insulin levels (C). Figure 1 D), and their insulin resistance index was also significantly increased; while compared with the olanzapine group mice, the insulin level of the GABA-treated group mice was significantly reduced, and the insulin resistance index decreased accordingly. Figure 1 E). The above results indicate that long-term olanzapine exposure in mice, combined with exogenous GABA supplementation, can improve olanzapine-induced insulin resistance.

[0040] <Example 2>

[0041] GABA can inhibit macrophage infiltration and M1 polarization in subcutaneous adipose tissue, thereby improving olanzapine-induced insulin resistance.

[0042] Experimental methods:

[0043] The number of macrophages and the proportion of M1 cells in mouse adipose tissue from Example 1 were detected by flow cytometry. The specific method is as follows: Mouse adipose tissue samples were weighed, placed in EP tubes, and minced with scissors. 500 μL of collagenase II, 500 μL of collagenase IV, 2 mL of DNase, and 2 mL of 1640 serum-free medium were added for digestion for 35 min. After filtering through a 250-mesh nylon sieve, the samples were centrifuged for 10 min (4℃, 500g). After centrifugation, the floating mature adipocytes on the upper layer were removed, and the bottom precipitate was collected. The cells were resuspended in staining buffer and counted to 1 × 10⁶ cells / mL. 6 / μL. Take 100μL of cell suspension, add 1μL of blocking agent, and incubate in the dark for 5 min. Add CD45, F4 / 80, CD11b, CD11c, and CD301 antibodies according to the recommended dosage, and incubate in the dark for 15 min. Add 1mL of 1X hemolysin without fixative, vortex to mix, and incubate in the dark for 10 min. Centrifuge for 5 min (4℃, 1500g), discard the supernatant, obtain cell pellet, add 200μL of sealing buffer, add 1μL of DAPI (1×), vortex to mix, and analyze.

[0044] Experimental results:

[0045] Flow cytometry results showed that, compared with the control group, the number of macrophages in the subcutaneous adipose tissue of mice in the olanzapine group was significantly increased, while the number of macrophages in the GABA-treated group was significantly decreased compared with the olanzapine group. Figure 2 A and B). Further analysis of M1 macrophages revealed that, compared with the control group, the olanzapine group showed a significant increase in the absolute number and proportion of pro-inflammatory M1 macrophages in the subcutaneous adipose tissue; while the GABA-treated group showed a significant decrease in the number and proportion of M1 macrophages compared with the olanzapine group. Figure 2 A and C, D), while the proportion of anti-inflammatory M2 macrophages increased significantly ( Figure 2 (A and E). The above results indicate that GABA can inhibit macrophage infiltration and M1 polarization in subcutaneous adipose tissue. And as... Figure 3 As shown, compared with the control group mice, the number of macrophages in the visceral adipose tissue of the olanzapine group mice was significantly increased. Figure 3 (A and B), while the GABA-treated group mice showed no significant difference in macrophage and M1 cell counts compared to the olanzapine-treated group mice. Figure 3 (A, C, D, E).

[0046] <Example 3>

[0047] GABA inhibited the migration of THP-1 mononuclear cells in ex vivo culture medium from subcutaneous adipose tissue of mice in the olanzapine group:

[0048] Experimental methods:

[0049] 0.5g of subcutaneous and visceral adipose tissue from mice in Example 1 was isolated, minced with ophthalmic scissors, and placed in 1640 medium containing 10% FBS and 1% penicillin antibiotics. The culture was incubated at 37°C and 5% CO2 for 48 hours. The conditioned medium was then collected and stored at 4°C for later use. Log-phase THP-1 cells were collected and live-cell fluorescently labeled using Calcein AM (Beyotime, C2012). The fluorescently labeled THP-1 cells were seeded in the upper chambers (8μm, 24-well plate) of a Tanswell plate at 3×10^5 cells per well. The conditioned medium described above was added to the lower chamber, and the cells were cultured for 24 hours. 500μL of Hoechst 33342 working solution was added to each well, and after incubation for 15 minutes, the cells were observed and photographed under a fluorescence microscope.

[0050] Experimental results:

[0051] like Figure 4 As shown, compared with the conditioned medium derived from subcutaneous tissue in the control group mice, the conditioned medium derived from subcutaneous adipose tissue in the olanzapine group mice significantly increased the migration of THP-1 from the upper chamber to the lower chamber, while the conditioned medium derived from subcutaneous adipose tissue in the GABA-treated group mice inhibited the migration of THP-1 from the upper chamber to the lower chamber. Figure 4 A). However, no similar results were observed when THP-1 cells were cultured in conditioned medium derived from mouse visceral fat. Figure 4 B). The above results indicate that GABA can inhibit the migration of THP-1 mononuclear cells induced by in vitro culture medium in subcutaneous adipose tissue of mice in the olanzapine group, further demonstrating that GABA can improve olanzapine-induced insulin resistance by inhibiting the infiltration of macrophages in subcutaneous adipose tissue.

[0052] <Example 4>

[0053] Supplementation with exogenous GABA can improve lipid metabolism disorders caused by long-term olanzapine exposure:

[0054] Experimental methods:

[0055] Using the mice from Example 1, the above experiments were performed at week 11. After anesthesia with pentobarbital, blood was collected and the mice were euthanized. Substances were then collected for subsequent HE staining: Inguinal white fat, epididymal white fat, interscapular brown fat, and liver were collected from the euthanized mice. They were fixed in fat-specific fixative and 4% paraformaldehyde, respectively. After dehydration, they were embedded in paraffin, sectioned, and stained with hematoxylin and eosin (HE) to observe the size of adipocytes and pathological changes related to lipid droplet aggregation.

[0056] Experimental results:

[0057] HE staining results of mouse subcutaneous adipose tissue showed ( Figure 5 Compared with the control group, mice in the olanzapine group showed significant proliferation of subcutaneous adipose tissue. Figure 5 A), tissue weight increased significantly ( Figure 5 B), individual fat cells are relatively large ( Figure 5 D), visceral fat also showed similar results ( Figure 5 C and D); meanwhile, mice in the olanzapine group showed ectopic fat deposition, with numerous lipid droplets appearing in brown adipose tissue and liver. Figure 5 D). Compared with the olanzapine group, the GABA-treated mice showed a significant decrease in subcutaneous adipose tissue weight and improved hyperplasia. Figure 5 (A and B), ectopic fat deposition in brown adipose tissue and liver of mice was also significantly alleviated. Figure 5 D). This indicates that supplementing with exogenous GABA can improve lipid metabolism disorders caused by long-term olanzapine exposure.

[0058] In summary, the inventors of this invention used a mouse model to confirm the effects of long-term olanzapine exposure on mouse body weight and pancreatic function, as well as the ameliorative effect of GABA. Using 4-week-old female C57BL / 6J mice, after intervention with saline, olanzapine, and GABA, respectively, it was found that compared with the olanzapine group, the GABA-treated group showed significantly reduced body weight and improved glucose tolerance and insulin sensitivity. Figure 1 The inventors further analyzed macrophage infiltration and M1 polarization in mouse adipose tissue, revealing how GABA alleviates olanzapine-induced insulin resistance. Flow cytometry was used to detect the number of macrophages and the proportion of pro-inflammatory M1 macrophages in mouse adipose tissue. The results showed that, compared with the control group, the olanzapine group had significantly increased macrophage infiltration and a significantly increased proportion of M1 macrophages in subcutaneous adipose tissue, while the GABA-treated group showed significantly improved macrophage infiltration and a significantly decreased proportion of M1 macrophages in subcutaneous adipose tissue. Figure 2 Furthermore, the inventors conducted in vitro culture of subcutaneous adipose tissue from mice and collected conditioned medium for monocyte migration experiments. The results showed that, compared with the control group, the conditioned medium in the olanzapine group promoted monocyte migration, while the conditioned medium derived from subcutaneous adipose tissue in the GABA-treated group significantly improved monocyte migration. Figure 4The above results indicate that GABA can inhibit macrophage infiltration in subcutaneous fat of mice, inhibit the polarization of pro-inflammatory M1 macrophages, and thus inhibit inflammation in adipose tissue, thereby improving olanzapine-induced insulin resistance. Therefore, GABA has the potential use in the preparation of drugs to prevent and treat olanzapine-induced insulin resistance, and can be used to prepare drugs that improve olanzapine-induced insulin resistance. Furthermore, the inventors of this invention further confirmed the effect of GABA in improving olanzapine-induced lipid metabolism disorders. Using 4-week-old female C57BL / 6J mice, after intervention with saline, olanzapine, and GABA respectively, it was found that the olanzapine group showed significant subcutaneous fat hyperplasia and significant ectopic fat deposition in brown adipose tissue and liver; while the above conditions were improved after GABA intervention. Figure 5 The above results indicate that exogenous GABA supplementation can significantly improve the adverse reaction of olanzapine-induced lipid metabolism abnormalities. Therefore, GABA has potential applications in the preparation of drugs for the prevention and treatment of olanzapine-induced lipid metabolism abnormalities, and can be used to prepare drugs that improve olanzapine-induced lipid metabolism abnormalities.

[0059] Although embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the specification and embodiments. It can be applied to various fields suitable for the present invention. Other modifications can be readily made by those skilled in the art. Therefore, without departing from the general concept defined by the claims and their equivalents, the present invention is not limited to the specific details and examples shown and described herein.

Claims

1. The use of gamma-aminobutyric acid (GABA) in the preparation of a medicament for the prevention and treatment of adverse reactions induced by olanzapine, wherein, Olanzapine-induced adverse reactions include insulin resistance and lipid metabolism disorders; GABA inhibits olanzapine-induced insulin resistance by suppressing macrophage infiltration in subcutaneous fat, inhibiting the polarization of pro-inflammatory M1 macrophages, and thus inhibiting inflammation in adipose tissue; GABA prevents olanzapine-induced lipid metabolism disorders by improving lipogenesis and ectopic deposition.

2. The application as described in claim 1, wherein, γ-Aminobutyric acid (GABA) is an active ingredient in single-component drugs or combination drugs.

3. The application as described in claim 1, wherein, Insulin resistance includes elevated serum insulin levels, impaired glucose tolerance, and decreased insulin sensitivity caused by adverse reactions to olanzapine.

4. The application as described in claim 1, wherein, Lipid metabolism disorders include fat hyperplasia and hypertrophy, as well as ectopic fat deposition in viscera, brown adipose tissue, and the liver.

5. The application as described in claim 2, wherein, The effective dose of γ-aminobutyric acid (GABA) is 50 mg / kg / day.

6. The application as described in claim 1, wherein, GABA refers to the small molecule metabolite of amino acids.

Images