Application of sodium mannoside in the preparation of drugs for the prevention or treatment of obesity and related metabolic diseases

Abstract

This invention discloses the application of sodium mannoside in the preparation of drugs for treating obesity and non-alcoholic fatty liver disease (NAFLD). Studies in this invention show that sodium mannoside has the effects of controlling body weight, improving glucose and lipid metabolism, enhancing insulin sensitivity, improving glucose tolerance, and preventing NAFLD. It can be used to prepare therapeutic drugs for metabolic diseases such as obesity caused by a long-term high-fat diet. Sodium mannoside can protect obese mice from liver lipotoxicity caused by a high-fat diet, providing more effective drugs for the prevention and treatment of obesity and NAFLD.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology. More specifically, it relates to the use of sodium mannoside in the preparation of drugs for the prevention or treatment of obesity and related metabolic diseases. Background Technology

[0002] Obesity refers to a significant degree of overweight and excessive fat accumulation, a condition caused by excessive accumulation of body fat, especially triglycerides. It is a chronic metabolic disease associated with type 2 diabetes, atherosclerosis, myocardial hypertrophy, various cardiovascular diseases, hepatic steatosis, and cancer. Obesity can cause many metabolic-related diseases, such as obesity, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD), leading to insulin resistance, impaired glucose tolerance, dyslipidemia, hepatic steatosis, and impaired liver function. NAFLD is primarily related to genetics, hepatitis B, and overnutrition. Excessive food intake leads to excess body fat that cannot be fully metabolized, resulting in fat accumulation in the liver and the development of NAFLD. NAFLD can cause liver enlargement, liver masses, and splenomegaly. Some individuals may experience sleep disturbances, right upper quadrant discomfort, and fatigue. A long-term imbalance between food intake and energy expenditure leads to NAFLD, for which there is currently no safe and effective drug treatment.

[0003] Currently, bariatric surgeries, such as Roux-en-Y gastric bypass and vertical sleeve gastrectomy, are among the most effective surgical treatments for obesity. However, these surgeries carry high risks and are expensive, and there are currently few drugs available for treating obesity and related metabolic diseases. Therefore, finding a safe and effective drug is crucial. Summary of the Invention

[0004] This invention provides the use of sodium mannitol in the preparation of drugs for the prevention or treatment of obesity and related metabolic diseases.

[0005] The purpose of this invention is to provide new applications for sodium mannitol.

[0006] The above-mentioned objective of this invention is achieved through the following technical solution:

[0007] This invention provides a novel application for sodium mannitol: it has a good therapeutic effect on reversing obesity and preventing non-alcoholic fatty liver disease. Sodium mannitol (GV971) is a low-molecular-weight acidic oligosaccharide compound prepared from marine brown algae extract and is a drug for treating Alzheimer's disease targeting the brain-gut axis. This invention establishes a diet-induced obesity mouse model through a high-fat diet. Studies show that sodium mannitol has a good therapeutic effect on obesity. In vivo experimental results confirm that sodium mannitol can significantly control the weight of obese mice and significantly improve metabolic syndrome caused by obesity, including significantly improving insulin resistance and enhancing insulin sensitivity, significantly improving impaired glucose tolerance, and significantly lowering lipids, mainly by reducing serum cholesterol and significantly reducing the accumulation of triglycerides in liver tissue. It has good biocompatibility and low toxicity.

[0008] Therefore, this invention provides the use of sodium mannoside in the preparation of drugs for the prevention or treatment of obesity or obesity-related metabolic diseases. Obesity specifically refers to diseases characterized primarily by weight gain and metabolic disorders.

[0009] Furthermore, the metabolic disease is weight gain and metabolic disorder, including insulin resistance, impaired glucose tolerance, and hepatic steatosis caused by lipid accumulation in the liver.

[0010] In particular, obesity can also lead to a variety of diseases (complications), and this invention shows that sodium mannitol has a good therapeutic effect on obesity and related metabolic syndromes. Therefore, timely control of obesity can effectively avoid a variety of diseases caused by obesity, such as non-alcoholic fatty liver disease, type 2 diabetes, atherosclerosis, and myocardial hypertrophy and other metabolic diseases.

[0011] Application of sodium mannitol in the preparation of drugs for weight control and metabolism improvement.

[0012] Sodium mannitol is used in the preparation of drugs that enhance insulin sensitivity, improve glucose tolerance, lower blood lipids, reduce lipid accumulation in liver tissue, and prevent hepatic steatosis.

[0013] Preferably, the blood lipids refer to serum cholesterol.

[0014] The use of sodium mannitol in the preparation of drugs for the prevention or treatment of non-alcoholic fatty liver disease caused by obesity.

[0015] The use of sodium mannoside in the preparation of drugs for the treatment or prevention of obesity.

[0016] The application of sodium mannoside in the preparation of drugs for treating metabolic syndrome. Metabolic syndrome refers to diseases mainly characterized by insulin resistance, impaired glucose tolerance, and dyslipidemia.

[0017] This invention also provides the use of sodium mannitol in the preparation of medicaments that reverse the process of obesity.

[0018] Furthermore, the reversal refers to controlling weight and improving metabolic syndrome caused by obesity, including lowering blood lipid levels, improving insulin resistance, enhancing insulin sensitivity, improving impaired glucose tolerance, and reducing lipid accumulation in liver tissue.

[0019] Furthermore, the reversal refers to lowering serum cholesterol levels and reducing the accumulation of triglycerides in liver tissue.

[0020] Preferably, the dosage form of the above-mentioned drug is a capsule, tablet, oral preparation, microcapsule preparation or injection.

[0021] The present invention has the following beneficial effects:

[0022] This invention provides a novel application of sodium mannitol in the preparation of drugs for treating obesity and non-alcoholic fatty liver disease-related metabolic disorders. Studies in this invention show that sodium mannitol has a significant therapeutic effect on high-fat diet-induced obesity in mice. Sodium mannitol can effectively reverse obesity; in vivo experiments confirm that sodium mannitol has a significant effect on controlling the weight of obese mice and significantly improves metabolic disorder syndromes in obese mice, including a significant decrease in insulin resistance, significant improvement in impaired glucose tolerance, and a reduction in serum cholesterol. It has a significant protective effect on the liver of obese mice, mainly including reducing the degree of fatty liver, reducing liver weight, reducing the liver-to-body ratio, reducing triglyceride levels in liver tissue, reducing lipid accumulation in liver tissue, reducing lipid droplets in liver tissue, reducing collagen fiber deposition in liver tissue, protecting the liver from fibrosis caused by fatty liver development, reducing serum AST and ALT levels, alleviating liver function damage caused by hepatic steatosis in obese mice, and protecting obese mice from hepatic lipotoxicity caused by a high-fat diet. It provides more effective drugs and treatment methods for the treatment of obesity and non-alcoholic fatty liver disease. Attached Figure Description

[0023] Figure 1 This is a body shape diagram of obese mice after treatment with sodium mannitol.

[0024] Figure 2 This is a graph showing the weight changes in obese mice after treatment with sodium mannitol.

[0025] Figure 3 This is a graph showing the dietary intake of obese mice after treatment with sodium mannitol.

[0026] Figure 4 This is a graph showing the glucose tolerance of obese mice after treatment with sodium mannitol.

[0027] Figure 5 This is a graph showing the insulin sensitivity of obese mice after treatment with sodium mannitol.

[0028] Figure 6 This is a graph showing serum cholesterol levels after treatment with sodium mannitol.

[0029] Figure 7 Image showing the appearance of liver tissue in obese mice after treatment with sodium mannitol.

[0030] Figure 8 Image showing liver tissue weight and liver-to-body ratio in obese mice after treatment with sodium mannitol.

[0031] Figure 9 This is a graph showing the triglyceride levels in the liver tissue of obese mice after treatment with sodium mannitol.

[0032] Figure 10 Images of liver tissue sections from obese mice treated with sodium mannitol, stained with Oil Red O, H&E, and Sirius Red.

[0033] Figure 11 This is a graph showing serum AST and ALT levels in obese mice after treatment with sodium mannitol.

[0034] Quantitative results in the figures are expressed as mean ± standard deviation (SD); all data were statistically analyzed using GraphPad Prism 9.4.0 (GraphPad Software, San Diego, USA); differences between groups were analyzed using one-way ANOVA; all bar charts, scatter plots, and curves were generated using GraphPad Prism 8.0 (GraphPad Software, San Diego, USA); *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, and P<0.05 were considered statistically significant. Detailed Implementation

[0035] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in this technical field.

[0036] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0037] Example 1: Establishment of an obese mouse model

[0038] This embodiment uses C57BL / 6J mice (purchased from Beijing Vital River Laboratory Animal Co., Ltd.). The mice were randomly divided into groups and fed uniformly for 26 weeks, divided into 5 groups:

[0039] (1) Normal control group (CON group, n=5): Maintained a normal diet for a total of 26 weeks. Starting from week 11, the carrier was given by gavage according to body weight. The rest of the time, the normal diet was maintained.

[0040] (2) Obesity model group (DIO group, n=5): High-fat diet was given from day 1, with free access to food and water for a total of 26 weeks; the carrier was given by gavage according to body weight from week 11 until week 26.

[0041] (3) Low-dose Ganlutna treatment group (DIO+GV-971(100mpk) group, n=5): High-fat diet was given from day 1, with free access to food and water for a total of 26 weeks; GV971(100mpk) was administered by gavage according to body weight from week 11 until week 26.

[0042] (4) Medium dose treatment group of sodium mannitol (DIO+GV-971 (200mpk) group, n=5): High-fat diet was given from day 1, with free access to food and water for a total of 26 weeks; GV971 (200mpk) was administered by gavage according to body weight from week 11 until week 26.

[0043] (5) High-dose Ganlutana group (DIO+GV-971(400mpk) group, n=5): High-fat diet was given from day 1, with free access to food and water for a total of 26 weeks; GV971(400mpk) was administered by gavage according to body weight from week 11 until week 26.

[0044] Example 2: The effect of sodium mannitol

[0045] (1) Using the mice constructed in Example 1, the weight and food intake were monitored and recorded daily when the mice started a high-fat diet. The average daily weight was calculated weekly to plot the weight change curve of the obese mice, and the average daily high-fat diet intake was calculated weekly to plot the diet intake curve, for a total of 26 weeks.

[0046] (2) At week 12 of modeling high-fat diet in mice and 2 weeks after treatment with mannitol, an oral glucose tolerance test (OGTT) was performed. Mice were fasted for 12 hours before the OGTT test. Blood samples were collected from the tail after 12 hours of fasting, and fasting glucose concentrations of each group of mice were measured using an ACCU-CHEK performa glucometer. The blood glucose concentration at 0 min in the oral glucose tolerance curve was recorded. Mice were then given glucose solution (2 g / kg) by gavage according to their body weight. Blood glucose concentrations of each group of mice were measured at 15 min, 30 min, 60 min, 90 min, and 120 min to plot the oral glucose tolerance curve (OGTT). The area under the oral glucose tolerance curve (AUC) was calculated using GraphPad Prism 9.4.0 software and statistical analysis of differences was performed to evaluate the ameliorative effect of GV-971 on impaired glucose tolerance in obese mice.

[0047] (3) After 23 weeks of modeling in mice on a high-fat diet (HFD) and 13 weeks of treatment with mannitol (GV-971), an insulin resistance test (ITT) was performed. Mice were fasted for 4 hours before the iPITT. Blood glucose levels were measured 4 hours after fasting and recorded as the blood glucose concentration at 0 min. Insulin was then injected intraperitoneally at a dose of 1 U / kg according to body weight. Blood samples were collected from the tail at 15 min, 30 min, 60 min and 90 min after injection. Glucose concentration was measured using an ACCU-CHEK performa glucometer. ITT curves were plotted using GraphPad Prism 9.4.0 software, the area under the ITT curve (AUC) was calculated and statistical analysis was performed to evaluate the effect of GV-971 on improving insulin resistance in obese mice.

[0048] At the end of week 26, mice in each group were euthanized, and adipose tissue was separated and weighed from various parts of the body. The weights of subcutaneous adipose tissue and visceral adipose tissue were statistically analyzed using GraphPad Prism 9.4.0 software. Liver tissue, muscle, heart, kidney, serum, and intestinal tissue were collected. The liver tissue of each group of mice was weighed, and the liver-to-body ratio was calculated based on the mouse's body weight. Statistical analysis of differences in liver tissue was then performed using GraphPad Prism 9.4.0 software. The lipid levels (TC, TG) and biochemical indicators of liver function damage (AST, ALT) in the serum of mice in each group were measured using a fully automated biochemical analyzer (Model 3100 Series AUTOMATIC ANALYZER). The frozen liver tissue was homogenized and lysed, and the triglyceride levels in the liver tissue of each group of mice were measured using a tissue triglyceride kit. The liver tissue was weighed and fixed with 4% paraformaldehyde for histological morphology, and then frozen sections were prepared. The pathological changes of steatosis and fibrosis in the mouse liver tissue were observed by Oil Red O staining, H&E staining, and Sirius Red staining.

[0049] The body size and physical characteristics of mice in each group after 26 weeks of high-fat diet (HFD) modeling and 16 weeks of mannostatin (GV-971) administration are as follows: Figure 1 As shown, compared with the normal control group (CON group), the obese model group (DIO group) mice were larger in size; compared with the DIO group, the obese mice treated with mannostatin were smaller in size and had good coat color, and the changes were dose-dependent, with the most significant changes in size observed in obese mice treated with high-dose and medium-dose mannostatin, followed by the changes in size observed in obese mice treated with low-dose mannostatin; compared with the normal control group (DIO group), the obese mice treated with high-dose mannostatin had a similar size to normal mice and good coat color.

[0050] The changes in body weight of mice in each group during the 26-week high-fat diet (HFD) modeling period and the 16-week administration of mannostatin (GV-971) are as follows: Figure 2As shown, starting from week 11, compared with the obesity model group (DIO group), the weight gain trend of obese mice treated with high, medium and low doses of mannitol all tended to be slow. The weight gain of obese mice treated with high, medium and low doses of mannitol was controlled and showed a dose-dependent effect. High-dose mannotrine intervention was most effective in treating obese mice. At week 5 of high-dose mannotrine intervention, the body weight of the GV-971 (400 mpk) group was significantly lower than that of the DIO group (*P < 0.05), and the difference persisted until week 9 of high-dose mannotrine intervention. At week 10 of high-dose mannotrine intervention, the body weight of the GV-971 (400 mpk) group was significantly lower than that of the DIO group (***P < 0.001), and the difference persisted until week 14 of high-dose mannotrine intervention. From week 15 to week 16 of high-dose mannotrine intervention, the body weight of the GV-971 (400 mpk) group was significantly lower than that of the DIO group (**P < 0.01). The effect of medium-dose mannotrine intervention in treating obese mice was second only to the high-dose mannotrine treatment group. Compared with the DIO group, the GV-971 (200 mpk) group showed slower weight gain and decreased weight after 10 weeks of medium-dose mannotrine intervention, but the difference was not statistically significant. At weeks 13 and 15 of medium-dose mannotrine intervention in obese mice, the weight of the GV-971 (400 mpk) group was significantly lower than that of the DIO group (*P < 0.05). At week 14 of medium-dose mannotrine intervention in obese mice, the weight of the GV-971 (200 mpk) group was significantly lower than that of the DIO group (**P < 0.01). During the 16-week period of low-dose mannotrine intervention in obese mice, compared with the DIO group, the weight gain of the GV-971 (100 mpk) group was slower, and the weight gain of obese mice was controlled, but the difference was not statistically significant. This indicates that mannitol has a weight-loss effect and can control the weight of obese mice without changing their diet.

[0051] The average daily high-fat diet intake of obese mice in each group during the 26-week high-fat diet (HFD) modeling period and the 16-week administration of mannitol (GV-971) is as follows: Figure 3 As shown, compared with the DIO group, there was no significant difference in the dietary intake of obese mice treated with mannitol in each group, and no adverse effects of mannitol on obese mice such as decreased appetite were found.

[0052] The results of oral glucose tolerance tests in mice after 12 weeks of high-fat diet (HFD) modeling and 2 weeks of administration of mannostatin (GV-971) are as follows: Figure 4As shown, compared with normal mice (CON group), obese mice exhibited significantly impaired glucose tolerance. The area under the oral glucose tolerance test (OGTT) curve (AUC) in the DIO group was significantly larger than that in the CON group, with a statistically significant difference (**P < 0.0001), indicating that the oral glucose tolerance of obese mice in the DIO group was severely impaired. Compared with the DIO group, the area under the oral glucose tolerance test (OGTT) curve (AUC) in the GV-971 (400 mpk) group was significantly smaller, with a statistically significant difference (**P < 0.01). When mice were administered glucose solution (2 g / kg) by gavage for 15 minutes according to their body weight, the blood glucose concentration in the GV-971 (400 mpk) group was significantly lower than that in the DIO group (**P < 0.01). Compared with the DIO group, the blood glucose concentration in obese mice in the GV-971 (200 mpk) group was significantly lower after 15 minutes of gavage (*P < 0.5). At 30 minutes, the blood glucose concentration in the GV-971 (400 mpk) group was lower than that in the DIO group (*P < 0.5). Obese mice treated with medium and high doses of mannitol for 2 weeks showed lower peak blood glucose levels in the oral glucose tolerance test than obese model mice, indicating that mannitol has an ameliorative effect on glucose intolerance in obese mice. Compared with the DIO group, the area under the oral glucose tolerance curve (AUC) was smaller in both the GV-971 (200 mpk) group and the GV-971 (100 mpk) group, but the difference was not statistically significant. This indicates that mannostatin can improve impaired glucose tolerance in obese mice in a dose-dependent manner, with high-dose mannostatin showing the most significant effect on improving oral glucose tolerance in obese mice.

[0053] The results of insulin tolerance test (ITT) in mice after 23 weeks of high-fat diet (HFD) modeling and 13 weeks of mannostatin (GV-971) administration are as follows: Figure 5As shown, compared with normal mice (CON group), obese mice exhibited significantly reduced insulin sensitivity and marked insulin resistance. The area under the insulin tolerance test (ITT) curve (AUC) in the DIO group was significantly larger than that in the CON group, with a statistically significant difference (*P<0.5), indicating that the DIO group showed significantly reduced insulin sensitivity and marked insulin resistance in obese mice. Compared with the DIO group, the area under the insulin tolerance test (ITT) curve (AUC) in the GV-971 (400mpk) group was significantly smaller, with a statistically significant difference (*P<0.5). Compared with the DIO group, the area under the insulin tolerance test (ITT) curve (AUC) in the GV-971 (200mpk) group was significantly smaller, with a statistically significant difference (*P<0.5). Compared with the DIO group, the GV-971 (100mpk) group showed a smaller area under the insulin tolerance test (AUC), but the difference was not statistically significant. Compared with the CON group, there was no significant difference in the area under the insulin resistance (ITT) curve (AUC) of obese mice treated with high, medium, and low doses of mannostatin, indicating that mannostatin can improve insulin resistance and enhance insulin sensitivity in obese mice. After intraperitoneal injection of insulin at a dose of 1 U / kg based on body weight for 15 minutes, the blood glucose concentration in the GV-971 (400 mpk) group was significantly lower than that in the DIO group (**P < 0.01); compared with the DIO group, the blood glucose concentration of obese mice in the GV-971 (200 mpk) group was significantly lower (*P < 0.5); the blood glucose concentration of obese mice in the GV-971 (100 mpk) group was significantly lower than that in the DIO group (**P < 0.01). At 30 min, the blood glucose concentration in the GV-971 (400 mpk) group was significantly lower than that in the DIO group (****P<0.0001); compared with the DIO group, the blood glucose concentration in obese mice in the GV-971 (200 mpk) group was significantly lower (***P<0.001); the blood glucose concentration in obese mice in the GV-971 (100 mpk) group was significantly lower than that in the DIO group 30 min after intraperitoneal injection of insulin at a dose of 1 U / kg based on body weight (*P<0.5). This indicates that mannostatin improves insulin resistance in obese mice in a dose-dependent manner, and that high-dose mannostatin has the most significant effect on improving oral glucose tolerance in obese mice.

[0054] The changes in blood lipids in mice after 26 weeks of high-fat diet (HFD) modeling and 16 weeks of mannostatin (GV-971) administration are as follows: Figure 6As shown, compared with normal mice in the CON group, the serum cholesterol concentration of obese mice in the DIO group was significantly increased, with a statistically significant difference (**P<0.01). Compared with the DIO group, the serum cholesterol concentration of obese mice in the high-dose mannostatin intervention group (GV-971 (400mpk) group) and the medium-dose mannostatin intervention group (GV-971 (200mpk) group) was significantly decreased, with statistically significant differences (**P<0.01). The serum cholesterol concentration of obese mice in the low-dose mannostatin administration group (GV-971 (100mpk) group) was lower than that in the DIO group, but the difference was not statistically significant. There was no significant difference in serum cholesterol concentration between obese mice treated with low-dose, medium-dose, and high-dose mannostatin interventions and normal mice. This indicates that mannostatin has a lipid-lowering effect and can significantly reduce serum cholesterol in obese mice without changing their diet.

[0055] The changes in liver appearance in mice after 26 weeks of high-fat diet (HFD) modeling and 16 weeks of mannostatin (GV-971) administration are shown in the figure. Figure 7 As shown, compared with normal mice in the CON group, the liver tissue of obese mice in the DIO group was yellowish in color, coarse in texture, and larger in volume. The livers of obese mice treated with low-dose, medium-dose, and high-dose mannitol, respectively, were redder, softer in texture, and smaller in volume than those of obese mice in the DIO group. Compared with the CON group, there were no significant differences in liver appearance among obese mice in the GV-971 (100 mpk), GV-971 (200 mpk), and GV-971 (400 mpk) groups. Liver weight and liver-to-body ratio of each group are shown in the figures. Figure 8 As shown, compared with normal mice in the CON group, the liver weight of obese mice in the DIO group was significantly heavier (**P<0.01); the liver tissue weight of obese mice treated with high-dose, medium-dose, and high-dose mannostatin was significantly lighter than that of obese mice in the DIO group (**P<0.01); there was no significant difference in liver weight among the obese mice in the mannostatin treatment groups compared with the CON group. Compared with normal mice in the CON group, obese mice in the DIO group had a significantly larger liver-to-body ratio (*P<0.05). Compared with the DIO group, obese mice in the GV-971 (100mpk), GV-971 (200mpk), and GV-971 (400mpk) groups had significantly smaller liver-to-body ratios (**P<0.01). Compared with normal mice in the CON group, obese mice in the GV-971 (100mpk), GV-971 (200mpk), and GV-971 (400mpk) groups had no significant differences in liver-to-body ratios.

[0056] Example 3: Lipid levels in mouse liver tissue

[0057] The triglyceride levels in mouse liver tissue treated in Example 2 were measured using a tissue triglyceride assay kit. The results are as follows: Figure 9 As shown, compared with normal mice in the CON group, the triglyceride level in the liver tissue of obese mice in the DIO group was significantly higher (***P<0.001); compared with the DIO group, the triglyceride level in the liver tissue of obese mice in the GV-971 (400mpk) group was significantly lower (****P<0.0001); the triglyceride level in the liver tissue of obese mice in the GV-971 (200mpk) group was significantly lower than that in the DIO group (**P<0.01); compared with the DIO group, the triglyceride level in the liver of obese mice in the GV-971 (100mpk) group was lower, but the difference was not statistically significant. This indicates that mannostatin reduces lipid accumulation and triglyceride levels in the liver of obese mice in a dose-dependent manner, with high-dose mannostatin showing the most significant effect, medium-dose mannostatin showing a noticeable effect, and low-dose mannostatin showing the next least significant effect.

[0058] Example 4: Pathological morphological changes in mouse liver tissue

[0059] Liver histopathology is one of the main methods for assessing hepatic steatosis. It mainly assesses lipid accumulation in liver tissue and observes lipid droplets through tissue H&E and Oil Red O staining, while Sirius Red staining of liver tissue is used to assess the degree of liver fibrosis.

[0060] The histopathological changes in liver tissue of mice after 26 weeks of high-fat diet (HFD) modeling and 16 weeks of administration of mannostatin (GV-971) are as follows: Figure 10As shown, compared with the CON group, the liver tissue of obese mice in the DIO group showed full-field lipid droplets in both Oil Red O staining and H&E staining. The liver tissue of obese mice in the DIO group contained a large number of lipid droplets and severe lipid accumulation, showing a certain degree of hepatic steatosis. Compared with normal mice in the CON group, the liver tissue of obese mice in the GV-971 (100 mpk) group showed occasional lipid droplets in Oil Red O staining and H&E staining. The liver tissue of obese mice in the GV-971 (200 mpk) group showed rare lipid droplets in Oil Red O staining and H&E staining. The liver tissue of obese mice in the GV-971 (400 mpk) group showed no significant difference in Oil Red O staining and H&E staining compared with normal mice in the CON group, and no cholestasis, inflammation, or necrosis was observed. Compared with normal mice in the CON group, the liver tissue of obese mice in the DIO group showed a large number of red collagen fibers in Sirius red stained sections, indicating a certain degree of fibrosis in the liver tissue. Compared with the CON group, there was no significant difference in Sirius red stained sections of liver tissue from obese mice in the GV-971 (100 mpk), GV-971 (200 mpk), and GV-971 (400 mpk) groups, and no obvious red collagen fibers were observed. In obese mice treated with mannostatin, lipid droplets in the liver tissue were significantly reduced, and no obvious collagen fibers were observed. Mannostatin reduced lipid accumulation in the liver tissue of obese mice and protected them from high-fat diet (HFD)-induced hepatic steatosis and fibrosis. Mannostatin has a preventive and therapeutic effect on fatty liver in obese mice.

[0061] Example 5: Biochemical indicators of mouse liver function, serum ALT and AST levels

[0062] Serum ALT and AST levels in mice after 26 weeks of high-fat diet (HFD) modeling and 16 weeks of mannitol (GV-971) administration were as follows: Figure 11As shown, compared with normal mice in the CON group, the serum ALT level of obese mice in the DIO group was significantly elevated, but there was no statistical difference due to the presence of abnormal values; the serum ALT levels of obese mice in the GV-971 (200 mpk) group and the GV-971 (400 mpk) group were not significantly different from those of normal mice in the CON group. Compared with normal mice in the CON group, the serum AST level of obese mice in the DIO group was significantly increased (**P<0.01), indicating significant liver function damage caused by hepatotoxicity in the DIO group. The serum AST levels of obese mice in the GV-971 (100mpk), GV-971 (200mpk), and GV-971 (400mpk) groups were not significantly different from those in normal mice in the CON group. Compared with obese mice in the DIO group, the serum AST levels of obese mice in the GV-971 (400mpk) and GV-971 (200mpk) groups were significantly decreased (**P<0.01). The serum AST level of obese mice in the GV-971 (100mpk) group was lower than that in the DIO group, but the difference was not statistically significant. This indicates that mannostatin simultaneously reduces serum AST and ALT levels in obese mice in a dose-dependent manner, with high doses showing the most significant therapeutic effect, medium doses showing a noticeable effect, and low doses showing the next least significant effect. Mannostatin not only shows no toxicity to the liver of obese mice but also reduces hepatic lipotoxicity in obese mice. Mannostatin also has a protective effect on liver function in obese mice.

[0063] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. The use of sodium mannoside in the preparation of drugs for the prevention or treatment of obesity or obesity-related metabolic diseases, characterized in that, The obesity-related metabolic diseases mentioned above are diseases caused by weight gain and metabolic disorders induced by obesity. The metabolic disorders are selected from insulin resistance, impaired glucose tolerance, and hepatic steatosis caused by lipid accumulation in the liver.

2. The application according to claim 1, characterized in that, Application of sodium mannitol in the preparation of drugs for weight control and metabolism improvement.

3. The application according to claim 1 or 2, characterized in that, Sodium mannitol is used in the preparation of drugs that enhance insulin sensitivity, improve glucose tolerance, lower blood lipids, reduce lipid accumulation in liver tissue, and prevent hepatic steatosis.

4. The application according to claim 3, characterized in that, The blood lipids refer to serum cholesterol.

5. Application of sodium mannitol in the preparation of drugs for the prevention or treatment of non-alcoholic fatty liver disease caused by obesity.

6. The application of sodium mannoside in the preparation of drugs to slow down or reverse the progression of obesity, characterized in that, The reversal refers to reducing weight gain, metabolic disorders, and hepatic steatosis caused by obesity; the mitigation refers to improving insulin resistance, improving impaired glucose tolerance, reducing serum cholesterol, reducing serum ALT and AST levels, reducing triglyceride accumulation in liver tissue, and reducing lipid droplets and fibrosis levels in liver tissue.

7. The use of sodium mannitol in the preparation of drugs for the treatment or prevention of obesity.

8. Application of sodium mannitol in the preparation of drugs for the treatment of metabolic syndrome.

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