动物造模,代谢综合征动物模型 z-bio 2021-05-27 837

　　Background: Metabolic syndrome is characterized by the development of at least three diseases: obesity, hyperglycemia, hypertension, or dyslipidemia. Metabolic syndrome has become a public health problem worldwide due to its increasing incidence. Depending on age, gender and race, the prevalence of epidemic diabetes in the world is between 10% and 84%. It is estimated that about 20-25% of adults suffer from metabolic syndrome. Metabolic syndrome is a collection of different states, so there is no single cause. Factors affecting the characteristics of metabolic syndrome can be genetic or environmental factors. Family history of type 2 diabetes, high blood pressure, insulin resistance, and ethnic background are genetic factors leading to a significant increase in the incidence of metabolic syndrome. In addition, aging is another important constant risk factor for metabolic syndrome. On the other hand, the environmental risk factors of metabolic syndrome are controllable. These include a sedentary lifestyle, lack of exercise and eating habits. Metabolic syndrome increases the risk of cardiovascular disease (CVD), type 2 diabetes, non-alcoholic fatty liver, cancer (liver, pancreas, breast, bladder), kidney and pancreas dysfunction. The harmful effects of metabolic syndrome have led researchers to develop new interventions to reduce the burden on the healthcare system. Due to the nature of many factors, it is difficult to choose a suitable experimental model that best describes the etiology of human MetS. Rats and mice are the most common animal models used to study metabolic syndrome. Various methods of inducing metabolic syndrome in rodents include diet control, genetic modification, and drugs. In this review, we will sort out and describe different animal models of metabolic syndrome. Diet-induced metabolic syndrome model: Many diets that can induce metabolic syndrome in animals have been reported. They include the use of a single type of diet or diet combination, such as high fructose, high sucrose, high fat, high fructose/high fat or high sugar/high fat diet. Diet affects systemic metabolism and regulation by affecting hormones, glucose metabolism and lipid metabolism pathways. In diet-induced metabolic syndrome models, the most commonly used rodents include SD rats, Wistar rats, C57BL/6J mice and hamsters.

　　Carbohydrate-rich diet: Carbohydrates can be divided into simple (such as monosaccharides) and complex (such as oligosaccharides and polysaccharides). Carbohydrates are one of the main energy sources (short-term fuel) in the body because they are easier to metabolize than fat. A sedentary lifestyle can lead to people with high energy intake but low physical activity, leading to increased energy storage, overweight, and ultimately obesity. When the intake of carbohydrates greatly exceeds the daily energy requirement, blood sugar levels are still high, and the pancreas secretes insulin, allowing the cells to absorb glucose. At this time, the mechanism of using glucose is as follows: (a) Glucose degradation during glycolysis; (b) Glucose is converted into glycogen in liver and muscle; (c) Insulin acts on adipose tissue and promotes and effectively inhibits fatty acid synthesis Release fatty acids. Excessive intake of carbohydrates for a long period of time will cause the blood sugar level to continue to rise. Therefore, insulin can lower blood sugar levels. Therefore, high diet carbohydrates are converted into fat storage. It also reduces insulin sensitivity. Many evidences show that high carbohydrate intake is closely related to insulin resistance. In animal models of metabolic syndrome, there is no information about the effect of carbohydrates on metabolism. Most diet plans are designed to combine high carbohydrates and high fats. There are two studies to track the metabolic changes in rats fed a high-carbohydrate and high-fat diet. This study used a high-carbohydrate and high-fat diet (including 39.5% condensed milk, 20% tallow, 17.5% fructose, 15.5% rat meal, 2.5% salt mixture, and 5% water) to establish Animal model. Researchers claim that it is closer to human pathology than other methods of inducing metabolic syndrome. After 16 weeks, the laboratory developed hypertension, decreased glucose tolerance, increased abdominal fat deposits, increased abdominal circumference, and changes in blood lipids. The results of some modified high-carbohydrate high-fat diet studies (35% sweet milk, 20% lard fat, 17.5% fructose, 20% powdered rat food, 2.5% salt mixture, 5% water) Similar to previous research. Ironically, it is reported that the combination of high carbohydrates and high fiber has the effect of lowering lipids and blood sugar. In clinical studies, a high-carbohydrate and high-fiber diet is recommended as a diet for diabetic patients. This is because this diet can lower blood sugar, insulin response, cholesterol and triglyceride levels after meals. Therefore, the composition and combination of a high-carbohydrate diet are important considerations for inducing metabolic syndrome. Diet rich in fructose: fructose, commonly known as fructose, is one of the monosaccharides of glucose and galactose. Nowadays, fructose is often used as a condiment to make food more delicious and attractive. Fructose in the diet has no biological needs, but an intermediate molecule in the process of glucose metabolism. Compared with glucose, the circulating levels of fructose in peripheral blood are very low. Interestingly, in the diet of diabetic patients, a small amount of fructose replaces sucrose and starch, which causes a hypoglycemic response. Unfortunately, the consumption of artificially sweetened beverages and foods is now an excessive consumption of fructose. Theoretically, the large amount of fructose entering the liver causes the accumulation of triglycerides and cholesterol due to its fat (lipogenic) properties, which in turn leads to insulin sensitivity, insulin resistance and impaired glucose tolerance. Intake of fructose can lead to a high intake of fructose in the liver. Fructose is converted to fructose-1-phosphate. Fructose involves multiple processes: (a) some fructose is converted into fatty acids and pyruvate, and (b) the other part produces trisaccharide phosphate. It is easily converted into glucose or glycogen. The inhibitory effect of fatty acids and (D) fructose liver on lipid peroxidation is beneficial for the synthesis of low-density lipoprotein (VLDL)-triglycerides and fatty acid esterification. As a result, this purified carbohydrate is rapidly absorbed and metabolized by the liver to produce glucose, glycogen, pyruvate, lactic acid, glycerol and acylglycerol molecules. The knowledge of fructose metabolism reveals the superiority of fructose ingestion over glucose or starch in inducing metabolic syndrome in animal models. Previous studies have shown that intake of glucose or starch is not as effective as intake of sugar in inducing metabolic syndrome. In addition, the mice fed fructose were heavier than the mice fed the same calorie starch. Excessive intake of fructose and energy, body weight, obesity, hypertriglyceridemia, hyperlipidemia, hypertension, impaired glucose tolerance, and long-term intake of experimental animals may cause metabolic syndrome. Studies have shown that rats fed a fructose-rich diet exhibited hypertension, decreased glucose tolerance and decreased insulin sensitivity, which accounted for 60% of total calories. Some studies claim that adding 10% fructose and high-dose fructose (accounting for 60% of the diet) in drinking water has the same effect as inducing hypertension and hyperlipidemia in male SD rats, but fructose is not as serious as high-dose fructose . In short, fructose is more like fat than human or animal carbohydrates. Low-dose fructose (10%) in drinking water is sufficient to induce metabolic syndrome in animals.

　　high sucrose diet: composed of fructose and glucose molecules. Sucrose and fructose have the same effect, making food more delicious. Sucrase can break it down into glucose and fructose. Both of these molecules are absorbed by their special transport mechanism. As described above, glucose fructokinase negatively regulates glucose uptake in glucose metabolism, which results in continuous binding of fructose to the glycolytic pathway. Fructose is an excellent substrate for fatty acid synthesis, so excess fructose will be converted into fat in the liver. Therefore, fructose is the main active ingredient, which can help animals develop metabolic syndrome after ingesting sucrose. In animal studies, adding 30% sucrose to drinking water increased the body weight, systolic blood pressure, insulin, triglycerides, total cholesterol, low-density cholesterol (LDL) and free fatty acids of male Wistar rats, thereby causing metabolic synthesis Levy. Show that there is a possibility. High sucrose is widely used to induce systemic insulin resistance in rats, thereby detecting high levels of plasma insulin. At the same time, animals with 32% sucrose in their drinking water showed hyperglycemia, hypertriglyceridemia, hypercholesterolemia and weight gain. Sucrose supplementation (77%), systolic blood pressure, plasma insulin and triglycerides increased significantly in rats. Kasim Karakas and others. Studies on fructose have shown that golden hamsters fed only fructose have increased levels of fasting non-esterified fatty acids and triglycerides in the plasma and liver. In addition, glucose tolerance decreased, and body weight and body fat increased significantly. Only rats fed fructose (15%) were detected, but no other groups fed soft drinks (10% sucrose) and diet soft drinks (no calories) were detected. .. In two different animal models, the response of fructose and sucrose feeding is different: SD and spontaneously hypertensive rats. These represent environmental syndrome and genetically acquired metabolic syndrome, respectively. Hyperfructoseemia leads to hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, hypertension and insulin resistance. At the same time, sucrose levels in spontaneously hypertensive rats only increase blood pressure and increase insulin resistance. The results of these previous studies indicate that high sucrose content is the key to the success of the metabolic syndrome animal model. However, since fructose exists in the form of free molecules, and fructose only contains 50% fructose and 50% glucose, fructose seems to be superior to the equivalent amount of sucrose in inducing metabolic syndrome. Fat-rich diet: Fat, also called triglycerides, is an ester composed of three fatty acid chains and glycerol. Fat metabolism begins with the lipolysis process. Large amounts of glycerin and fatty acids diffuse freely into the blood. Plasma free fatty acids are the main substrate of VLDL triglycerides in the liver. About 70% of the released free fatty acids are re-esterified to form triglycerides (lipogenesis). The rate of re-esterification depends on the rate of production of fatty acid 3-phosphate glyceride by glycolysis and release from fat cells. Freedom and reorganization can esterify fatty acids (triglycerides) to form very low-density lipoproteins, thereby helping fats circulate in the blood in water-based solutions. Many researchers use different types of high-fat diets, which account for 20-60% of total energy. The source of fat is vegetable oil (corn, safflower, olive oil, etc.) or animal fat (tallow, lard, etc.). High-fat diets are widely used for metabolic syndrome in laboratory animals. More specifically, high-fat diets are widely used to induce obesity in animals. Studies have shown that a high-fat diet helps promote blood sugar levels, insulin resistance, dyslipidemia, and an increase in free fatty acids in the blood. Ghibaudi et al. The purpose of this study is to study the long-term effects of dietary fat on rat obesity and various fat content (10%, 32% and 45%) in metabolism. The results of the study showed that energy intake, weight gain, fat mass, blood sugar, cholesterol, triglycerides, free fatty acids, leptin and insulin levels increased in a dose-dependent manner with the increase in dietary fat. In addition, mice fed a high-fat (60%) diet showed significant weight gain, total fat pads, plasma triglycerides, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein cholesterol levels. Another animal model fed high fat showed total cholesterol, elevated low-density lipoprotein and unesterified cholesterol. Subsequent studies found that high fat intake increased the body weight, total cholesterol and leptin levels of male C57BL/6 mice. Another recent study showed that compared with high-fat diet, mice on a high-fat diet increased body weight, blood lipids, plasma insulin and insulin resistance. The increased formation of very low-density lipoprotein helps to assemble triglycerides from a high-fat diet, which leads to liver synthesis. High levels of very low-density lipoprotein cholesterol can lead to obesity, dyslipidemia and cholesterol accumulation in the arteries. The accumulation of triglycerides in the liver can cause insulin resistance. Genetic model of metabolic syndrome: In addition to the animal model of metabolic syndrome caused by diet, it is also necessary to establish a genetic animal model to study the etiology of metabolic syndrome caused by genetic factors. These genetic models of metabolic syndrome can save time because the onset of metabolic syndrome is significantly shorter than the onset of diet-induced metabolic syndrome. Leptin or leptin receptor-deficient rodent models are used as experimental models for genetic obesity and diabetes. Many animal models have been developed, including leptin-deficient mice (ob/ob), leptin receptor-deficient mice (db/db), (ZF) rats and diabetic fat (ZDF) rats. Leptin is an anti-obesity hormone that binds to leptin receptors. It is secreted by mature fat cells and is proportional to the size of fat deposits. Circulating leptin is absorbed by the hypothalamus, thereby reducing food intake and appetite, and increasing energy expenditure through various signaling pathways. Therefore, the occurrence of obesity in these models is mainly due to abnormal leptin signal transduction, which leads to bulimia nervosa (food craving) and reduces energy expenditure. Leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice are autosomal recessive models of the leptin gene (chromosome 6) and leptin receptor gene (chromosome 4), respectively. Leptin deficiency (ob/ob) mice will develop obesity, hyperinsulinemia and hyperglycemia without hypertension or dyslipidemia. No hypertension and dyslipidemia occurred after 38 weeks. Mice lacking leptin receptors (db/db) developed obesity, hyperglycemia and dyslipidemia, but did not have hypertension. (GK) The rat leptin resistant animal model is considered to be the best non-obese type 2 diabetes model. They spontaneously develop hyperleptinemia, hyperglycemia, reduce appetite, increase β-cell function, increase gluconeogenesis and promote visceral fat accumulation. Among all these leptin and leptin receptor-related animal models, ZF, ZDF, and DS/obese rats are suitable models because these rats exhibit all the symptoms of metabolic syndrome.

　　Drug/chemically induced metabolic syndrome model: Glucocorticoid-induced metabolic syndrome: Endogenous glucocorticoid is a natural stress hormone secreted by the adrenal glands. Exogenous glucocorticoids are used to treat various human diseases, such as autoimmune diseases and cancer. It can also be used to prevent rejection in organ transplants. However, glucocorticoid therapy may have adverse side effects, such as weight gain, impaired glucose tolerance, decreased calcium homeostasis, osteoporosis, cataracts, and effects on the central nervous system. In animal models, endogenous and exogenous glucocorticoids are used to develop metabolic syndrome. The metabolic syndrome caused by glucocorticoids directly affects various tissues and organs (liver, muscle, fat, kidney, etc.) through several mechanisms: (1) Glucocorticoids are the mature fat cells of pre-adipocytes and promote differentiation; (2) ) Glucocorticoids can increase lipolysis (3) Glucocorticoids may promote muscle growth and increase the hydrolysis of free fatty acids. Amino acids induce activation of the mammalian target of rapamycin (mTORC1), leading to the phosphorylation of insulin receptor substrate (IRS-1) and leading to the development of insulin resistance. (4) Glucocorticoids promote the liver and cause hyperglycemia and gluconeogenesis. (5) The non-specific binding of glucocorticoids and their receptors will cause sodium retention in the kidneys, and increase the plasma volume with potassium excretion, retention of body fluids and increased blood pressure. Using experimental animals, glucocorticoid-induced metabolic syndrome has been achieved through a variety of methods, including eating, intraperitoneal daily 

glucocorticoid injection or surgical implantation of particles. All these different routes of administration of glucocorticoids lead to similar results. Corticosterone levels are related to animal food intake, weight gain, abdominal fat accumulation, severe fasting hyperglycemia, insulin resistance, impaired glucose tolerance, high blood pressure, dyslipidemia, as well as visceral fat, liver tissue and deposits in the bones, and increase in muscle Lipids. Metabolic syndrome caused by antipsychotics: Antipsychotics are drugs used to treat neuropsychiatric diseases such as schizophrenia, depression, and bipolar disorder. Antipsychotics have a high incidence of metabolic syndrome, which is mainly manifested as weight gain, increased visceral fat, impaired glucose tolerance and insulin resistance. However, the exact underlying mechanism of metabolic syndrome caused by antipsychotics remains a mystery. The currently proposed mechanism is that weight gain caused by antipsychotic drugs contributes to the development of diabetes and dyslipidemia. The second-generation antipsychotic drug olanzapine interacts with the intestinal flora through intraperitoneal injection or oral administration in rats and mice, thereby increasing body weight, increasing plasma free fatty acids, infiltration of adipose tissue macrophages and internal organs, leading to fat deposition. Since antipsychotics are important drugs for the treatment of mental illnesses, it is necessary to continue research to clarify the mechanism of metabolic syndrome caused by antipsychotics and avoid side effects.

　　Conclusion: In conclusion, the advantage of using animal models to study metabolic syndrome lies in the ability to monitor the histological, functional, biochemical and morphological changes of metabolic syndrome. In addition to similar to the pathophysiology of human metabolic syndrome, good animal models also need to be reproducible, simple, reliable, and have minimal disadvantages.