Application of N-acetylglutamine in preparation of medicine for treating obesity or reducing obesity-related metabolic indexes or MAFLD
By using N-acetylglutamine to promote fat breakdown and utilization, the problems of large side effects and poor compliance of existing obesity and MAFLD treatment drugs are solved, achieving safe and effective weight loss and liver function improvement.
Patent Information
- Application Number
- CN202510804962.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-17
- Publication Date
- 2025-08-15
AI Technical Summary
Existing medications for obesity and metabolic-associated fatty liver disease (MAFLD) suffer from significant side effects, poor patient compliance, and limited long-term efficacy. There is a lack of drugs that can effectively reduce systemic fat accumulation and improve hepatic steatosis.
Using N-acetylglutamine as the active ingredient, it can be administered orally or via intraperitoneal injection to promote fat breakdown and utilization, reduce the mass of visceral and subcutaneous white fat, improve liver function, and lower serum alanine aminotransferase and alkaline phosphatase levels.
N-acetylglutamine can specifically reduce weight, improve liver function, and lower serum levels, without side effects such as nausea, vomiting, diarrhea, and urinary tract infections, thus improving patient compliance.
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Abstract
Description
Technical Field
[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to the use of N-acetylglutamine in preparing a drug for treating obesity or alleviating obesity-related metabolic indicators or MAFLD. Background Art
[0002] Obesity and its related metabolic diseases, especially metabolic-associated fatty liver disease (MAFLD, formerly known as non-alcoholic fatty liver disease, NAFLD), have become a major public health challenge worldwide. Obesity refers to abnormal or excessive fat accumulation that has adverse effects on health. In clinical practice, the body mass index (BMI) is often used to assess the degree of obesity in patients. The 2024 Obesity Diagnosis and Treatment Guidelines of the National Health Commission of China stipulate that 24 kg / m 2 <BMI≤28kg / m 2 Adults are overweight, with a BMI > 28 kg / m 2 Of adults are obese. According to the WHO, the number of overweight or obese people worldwide exceeds 1 billion, and over 50% of these patients have MAFLD. Obesity is not only a core driver of metabolic disease but is also closely linked to the incidence of MAFLD. The global prevalence of MAFLD is as high as 25%-30%, exceeding 50% among overweight and obese people. China is one of the countries with the heaviest burden of MAFLD globally, with the adult MAFLD prevalence surging from 3.9% in 1995 to 43.7% in 2015, and currently stands at 29.2% nationwide.
[0003] Adipose tissue is unevenly distributed throughout the body. When sugar, lipid, and amino acid metabolism is disrupted (i.e., metabolic dysfunction occurs), excessive fat accumulates in the liver, leading to fatty degeneration of liver cells and the development of MAFLD. Multiple factors, including genetics, excessive diet, and lack of exercise, can contribute to metabolic dysfunction. Therefore, current treatment strategies primarily focus on lifestyle interventions, such as dietary adjustments and increased physical activity. However, patient compliance is poor, and long-term effectiveness is limited. Furthermore, appetite-suppressing GLP-1 receptor agonists (such as liraglutide and semaglutide) have side effects such as nausea, vomiting, depression, and muscle loss. Drugs that inhibit intestinal lipid absorption (such as orlistat) have side effects such as bloating and steatorrhea. SGLT2 inhibitors, which inhibit renal glucose reabsorption, have side effects such as urinary tract infections.
[0004] Therefore, developing a new drug that targets excessive body fat accumulation and improves MAFLD symptoms while reducing weight has become an urgent need in the field of metabolic diseases worldwide. Summary of the Invention
[0005] The present invention aims to provide the use of N-acetylglutamine in the preparation of a drug for treating obesity or reducing obesity-related metabolic indicators or MAFLD. The N-acetylglutamine provided by the present invention can reduce fat weight, treat obesity, improve liver steatosis, and improve insulin sensitivity and glucose tolerance, providing an experimental basis for the development of new drugs targeting the symptoms of obesity and MAFLD.
[0006] The present invention provides the use of N-acetylglutamine in preparing a medicine for treating obesity or alleviating obesity-related metabolic indicators or MAFLD.
[0007] Furthermore, the indicator for obesity is body mass index (BMI) > 28 kg / m 2 .
[0008] Furthermore, obesity-related metabolic indicators include the proportion of total body fat and the weight of visceral or subcutaneous white fat.
[0009] Furthermore, obesity-related metabolic indicators include fatty degeneration of liver cells, fat content in liver cells, and serum alanine aminotransferase and alkaline phosphatase levels.
[0010] Furthermore, the oral dosage form is one of tablets, capsules, pills, powders, granules or oral liquids.
[0011] Compared with existing drugs, the beneficial effects of the present invention are:
[0012] This invention demonstrates for the first time that N-acetylglutamine exhibits significant potential in the treatment of obesity and MAFLD. Specifically, N-acetylglutamine can promote the decomposition and utilization of fat, reduce the mass of visceral and subcutaneous white fat, and reduce body weight; at the same time, it reduces fat accumulation in the liver and improves liver function, as manifested by lowering serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels.
[0013] Compared with current therapeutic drugs for obesity and MAFLD, N-acetylglutamine can specifically target excessive lipid accumulation and has stronger targeting. N-acetylglutamine is a natural metabolite present in both food and the human body and has high biosafety. In addition, compared with therapeutic drugs that suppress appetite and inhibit food absorption, N-acetylglutamine does not cause side effects such as nausea, vomiting, diarrhea, and urinary tract infections. BRIEF DESCRIPTION OF THE DRAWINGS
[0014] Figure 1 The concentrations of N-acetylglutamine in the blood and tissues of mice after oral and intraperitoneal administration in Example 1 are shown.
[0015] Figure 2 N-acetylglutamine reduces body weight in high-fat diet-induced obese mice after oral and intraperitoneal administration.
[0016] Figure 3 Figure 3. Changes in metabolic cage assay in HFD mice after intraperitoneal administration of N-acetylglutamine.
[0017] Figure 4 Oral administration of N-acetylglutamine solution improves fatty liver and lipid metabolism in obese mice induced by a high-fat diet.
[0018] Figure 5 N-acetylglutamine treatment improves glucose tolerance and insulin sensitivity in high-fat-induced obese mice. DETAILED DESCRIPTION
[0019] In order to enable those skilled in the art to better understand the present invention, the following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts should fall within the scope of protection of this application.
[0020] It should be noted that the terms "including" and "having" and any variations thereof in the specification and claims of this application and the above-mentioned drawings are intended to cover non-exclusive inclusions. For example, a process, method, system, product or apparatus that includes a series of steps or units is not necessarily limited to those steps or units clearly listed, but may include other steps or units that are not clearly listed or are inherent to these processes, methods, products or apparatuses.
[0021] The experimental methods described in the examples of the present invention are conventional methods unless otherwise specified. The materials, reagents, etc. used in the following examples are all commercially available unless otherwise specified.
[0022] Example 1 N-acetylglutamine is absorbed into the blood circulation as a prototype molecule
[0023] Experimental Animals: Male C57BL / 6J mice (8 weeks old) were purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd. All animal experiments were approved by the Experimental Animal Care Committee of Nanjing Medical University. All experimental animals were housed in a barrier facility at the Experimental Animal Center of Nanjing Medical University in a clean environment with a temperature of (21 ± 2)°C, a humidity of (35 ± 2)%, and 12 h:12 h daylighting. They had free access to food and water, using sterile water prepared by the Experimental Animal Center.
[0024] Experimental methods:
[0025] 1) All mice were fasted but not watered for 12 hours the night before;
[0026] 2) The next day, blood was collected from the eyeballs of mice in the fasting group (0 minutes), centrifuged at 3000 rpm for 15 minutes at 4°C, and the serum was collected and frozen at -80°C. At the same time, small intestinal tissue was collected and quickly frozen in liquid nitrogen and then frozen at -80°C.
[0027] 3) N-acetylglutamine (300 mg / kg) was administered orally or intraperitoneally on an empty stomach. Mice were sacrificed 30 or 60 minutes after administration. Blood was collected from the orbits and centrifuged at 3000 rpm for 15 minutes at 4°C. Serum was collected and frozen at -80°C. Small intestinal tissue was also collected and quickly frozen in liquid nitrogen and stored at -80°C.
[0028] 4) Targeted mass spectrometry was used to detect N-acetylglutamine concentrations in the serum and intestine of mice at fasting, 30 minutes, and 60 minutes after administration
[0029] 5) Statistical analysis: All data in this experiment were expressed as mean ± standard deviation (±s). The differences between the groups were analyzed using the t-test, and P < 0.05 was used as the reference standard for statistical differences.
[0030] Figure 1 Figures 1 and 2 show the concentrations of N-acetylglutamine in blood and tissues after oral and intraperitoneal administration. Figure A shows the time-dependent changes in N-acetylglutamine concentration in mouse serum following oral administration of N-acetylglutamine. Figure B shows the time-dependent changes in N-acetylglutamine concentration in mouse intestinal tissue following oral administration of N-acetylglutamine. Figure C shows the time-dependent changes in N-acetylglutamine concentration in mouse serum following intraperitoneal administration of N-acetylglutamine.
[0031] Experimental results: The results show that N-acetylglutamine is stably absorbed orally. After oral administration, N-acetylglutamine can be absorbed into the blood unchanged and is not degraded in the intestine, showing excellent bioavailability. This property makes it suitable for development into an oral formulation to improve patient compliance.
[0032] Example 2 N-acetylglutamine treatment reduces body weight in high-fat diet-induced obese mice
[0033] Experimental Animals: Male C57BL / 6J mice were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd. All animal experiments were approved by the Experimental Animal Management Committee of Nanjing Medical University. All experimental animals were housed in a barrier facility at the Experimental Animal Center of Nanjing Medical University in a clean environment with a temperature of (21 ± 2)°C, a humidity of (35 ± 2)%, and 12 h:12 h daylighting. They had free access to food and water, which was sterile water prepared by the Experimental Animal Center.
[0034] Experimental methods:
[0035] 1) Intraperitoneal Injection: The treatment group received NAG solution (100 or 300 mg / kg, prepared in dd / water) every other day, while the control group received an equal volume of dd / water. Body weight was monitored regularly.
[0036] 2) Drinking Water Administration: Drinking water (3% (w / v) NAG in dd water) was changed daily in the treatment group, while the same volume of dd water was replaced daily in the control group. Body weight was monitored regularly.
[0037] 3) After drug administration, conduct a metabolic cage experiment to monitor the mice's diet, drinking water, respiration, activity, metabolism, etc.
[0038] 4) At the observation endpoint, the liver, epididymal fat, inguinal fat, brown fat, and quadriceps muscle tissues of the mice were collected and weighed.
[0039] Figure 2 N-acetylglutamine reduces body weight in mice induced by high-fat diet-induced obesity after oral and intraperitoneal administration. Panel A shows body weight changes in HFD mice after intraperitoneal administration of N-acetylglutamine. Panel B shows changes in liver, inguinal fat, epididymal fat, quadriceps femoris, and brown adipose tissue weights in HFD mice after intraperitoneal administration of N-acetylglutamine. Panel C shows changes in liver, inguinal fat, epididymal fat, quadriceps femoris, and brown adipose tissue weight as a percentage of body weight in HFD mice after intraperitoneal administration of N-acetylglutamine. Panel D shows body weight changes in HFD mice after oral administration of N-acetylglutamine. Panel E shows changes in liver, inguinal fat, epididymal fat, quadriceps femoris, and brown adipose tissue weights in HFD mice after oral administration of N-acetylglutamine. Panel F shows changes in liver, inguinal fat, epididymal fat, quadriceps femoris, and brown adipose tissue weight as a percentage of body weight in HFD mice after oral administration of N-acetylglutamine.
[0040] Figure 3 Figures 2 and 3 show changes in metabolic cage measurements in HFD mice after intraperitoneal administration of N-acetylglutamine. Panels AC show that HFD mice consumed more oxygen in metabolic cages after intraperitoneal administration of N-acetylglutamine. Panels DF show that HFD mice exhaled more carbon dioxide in metabolic cages after intraperitoneal administration of N-acetylglutamine. Panel G shows that the calculated respiratory exchange ratio (RER) values in metabolic cages in HFD mice were closer to 0.7 after intraperitoneal administration of N-acetylglutamine. Panels HJ show that HFD mice produced more heat in metabolic cages after intraperitoneal administration of N-acetylglutamine.
[0041] Results: The NAG-treated mice showed significant reductions in liver, epididymal, and inguinal subcutaneous fat. Even after adjusting for weight loss, these reductions persisted. Metabolic cage experiments revealed no significant changes in food intake, but increased oxygen consumption and exhaled CO₂, with a relative oxygen relieving rate (RER) approaching 0.7, suggesting that NAG enhances fat utilization in mice.
[0042] Example 3 Oral administration of N-acetylglutamine solution improves fatty liver and lipid metabolism in obese mice induced by a high-fat diet
[0043] Experimental Animals: Male C57BL / 6J mice were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd. All animal experiments were approved by the Experimental Animal Management Committee of Nanjing Medical University. All experimental animals were housed in a barrier facility at the Experimental Animal Center of Nanjing Medical University in a clean environment with a temperature of (21 ± 2)°C, a humidity of (35 ± 2)%, and 12 h:12 h daylighting. They had free access to food and water, which was sterile water prepared by the Experimental Animal Center.
[0044] Experimental methods:
[0045] 1) Administration by drinking water: The drinking water of the treatment group (3% (w / v) NAG, prepared in dd water) was replaced every day, while the same volume of dd water was replaced every day in the control group.
[0046] 2) Observe the endpoint, extract liver tissue, perform liver oil red O staining and HE staining, and observe the fatty liver lesions
[0047] 3) Blood was collected from the eye sockets, serum was separated, and liver enzymes including alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were detected by an automatic biochemical analyzer.
[0048] Figure 4 Oral administration of N-acetylglutamine solution improves fatty liver and lipid metabolism in mice with high-fat diet-induced obesity. Figure A shows a gross comparison of liver tissue between mice in the oral N-acetylglutamine group and the control group. Figure B shows changes in serum ALT and ALP levels in HFD mice after oral N-acetylglutamine administration. Figure C shows changes in H&E and Oil Red O staining of liver sections from HFD mice after oral N-acetylglutamine administration.
[0049] Experimental results: In a high-fat diet-induced fatty liver model, N-acetylglutamine can significantly reduce liver lipid deposition, improve liver function, reduce liver inflammation and fibrosis markers, and reverse fatty liver lesions.
[0050] Example 4 N-acetylglutamine treatment improves glucose tolerance and insulin sensitivity in high-fat-induced obese mice
[0051] Experimental Animals: Male C57BL / 6J mice were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd. All animal experiments were approved by the Experimental Animal Management Committee of Nanjing Medical University. All experimental animals were housed in a barrier facility at the Experimental Animal Center of Nanjing Medical University in a clean environment with a temperature of (21 ± 2)°C, a humidity of (35 ± 2)%, and 12 h:12 h daylighting. They had free access to food and water, which was sterile water prepared by the Experimental Animal Center.
[0052] Experimental methods:
[0053] 1) Intraperitoneal Injection: The treatment group received NAG solution (100 or 300 mg / kg, prepared in dd / water) every other day, while the control group received an equal volume of dd / water. Body weight was monitored regularly.
[0054] 2) Drinking Water Administration: Drinking water (3% (w / v) NAG in dd water) was changed daily in the treatment group, while the same volume of dd water was replaced daily in the control group. Body weight was monitored regularly.
[0055] 3) After administration, the mice were subjected to intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT) to detect glucose metabolism and insulin sensitivity.
[0056] Figure 5 N-acetylglutamine treatment improves glucose tolerance and insulin sensitivity in high-fat-induced obese mice. Figures AB show the blood glucose curves and the area under the curve (AUC) of HFD mice following intraperitoneal injection of N-acetylglutamine in an IPGTT experiment. Figures CD show the blood glucose curves and the area under the curve (AUC) of HFD mice following intraperitoneal injection of N-acetylglutamine in an IPGTT experiment. Figure EF shows the blood glucose curves and the area under the curve (AUC) of HFD mice following intraperitoneal injection of N-acetylglutamine in an ITT experiment. Figure GH shows the blood glucose curves and the area under the curve (AUC) of HFD mice following oral administration of N-acetylglutamine in an IPGTT experiment. Figure IJ shows the blood glucose curves and the area under the curve (AUC) of HFD mice following oral administration of N-acetylglutamine in an IPGTT experiment. Figure KL shows the blood glucose curves and the area under the curve of HFD mice following oral administration of N-acetylglutamine in an ITT experiment.
[0057] Experimental results: N-acetylglutamine can improve the insulin sensitivity of metabolic tissues, enhance the uptake and utilization of glucose by peripheral tissues, and thus improve insulin resistance.
[0058] The above describes in detail the preferred embodiments of the present invention. It should be understood that those skilled in the art can make numerous modifications and variations based on the concepts of the present invention without inventive effort. Therefore, any technical solutions that can be derived by those skilled in the art through logical analysis, reasoning, or limited experimentation based on the concepts of the present invention and the prior art should be within the scope of protection defined by the claims.
Claims
1. Use of N-acetylglutamine in the preparation of drugs for treating obesity or alleviating obesity-related metabolic indicators or metabolic-associated fatty liver disease (MAFLD).
2. The use according to claim 1, characterized in that: The obesity index is BMI>28kg / m 2 .
3. The use according to claim 1, characterized in that: The obesity-related metabolic indicators include the body fat ratio and the weight of visceral or subcutaneous white fat.
4. The use according to claim 1, characterized in that: The obesity-related metabolic indicators include liver cell fatty degeneration, liver cell fat content, serum alanine aminotransferase and alkaline phosphatase levels.
5. The use according to claim 1, characterized in that: The oral dosage form is one of tablets, capsules, pills, powders, granules or oral liquids.