代谢综合征,动物模型 z-bo 2020-12-07 316

　　Background: Metabolic syndrome is characterized by the occurrence of at least the following three diseases: obesity, hyperglycemia, hypertension, or dyslipidemia. Metabolic syndrome has become a public health care problem worldwide due to its increasing incidence. The prevalence of epidemic diabetes in the world ranges from 10 to 84%, depending on age, gender, and race. Approximately 20-25% of adults are estimated to have metabolic syndrome. Metabolic syndrome is a collection of various conditions, so it has no single cause. Factors affecting the characteristics of metabolic syndrome can be hereditary or environmental. Family history of type II 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 unalterable 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 and bladder), kidney and pancreas dysfunction. The harmful effects of metabolic syndrome have attracted researchers to develop new interventions to reduce the burden on the medical system. Due to the nature of multiple factors, it is quite challenging to choose an appropriate experimental model that best represents the pathogenesis of human MetS. Rats and mice are used to study the most common animal models of metabolic syndrome. Various methods of inducing metabolic syndrome in rodents include diet manipulation, genetic modification, and drugs. In this review, we collate and discuss various animal models of metabolic syndrome.

　　Diet-induced metabolic syndrome model: Many dietary methods that can induce metabolic syndrome in animals have been reported. They include the use of a single type of diet or a combination of diets, 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/6 J 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 sources of energy in the body (short-term fuel) because they are easier to metabolize than fat. Adopting a sedentary lifestyle causes individuals to enter a state of high energy intake, but low physical activity, thereby increasing energy storage, overweight and ultimately obesity. When the intake of carbohydrates greatly exceeds the daily energy requirement, the blood glucose concentration will remain at a high level, and the pancreas will secrete insulin for the cells to take up glucose. At this time, the mechanism of using glucose is: (a) the decomposition of glucose during glycolysis; (b) the conversion of glucose into glycogen in the liver and muscle; (c) insulin acts on adipose tissue to promote fatty acid synthesis and inhibit effective The release of fatty acids. Long-term excessive consumption of carbohydrates can lead to persistently high blood sugar levels. Therefore, insulin can lower blood sugar. Therefore, high dietary carbohydrates are converted into fat storage. Insulin sensitivity also decreases. A lot of evidence shows that high carbohydrate intake is closely related to insulin resistance. There is no information on the metabolic effects of carbohydrates on animal models of metabolic syndrome. Most diet plans are designed with a combination of high carbohydrate and high fat. Two studies tracking the metabolic changes of rats on a high-carbohydrate and high-fat diet are available. In this study, a high-carbohydrate and high-fat diet (containing 39.5% condensed milk, 20% tallow, 17.5% fructose, 15.5% powdered rat food, 2.5% salt mixture, 5% water) was used to induce an animal model. Researchers claim that it is closer to the human disease state than other methods of inducing metabolic syndrome. After 16 weeks, the experimental animals developed hypertension, impaired glucose tolerance, increased abdominal fat deposition, increased abdominal circumference and changes in blood lipids. Some modified high-carbohydrate high-fat diet studies (35% sweetened condensed milk, 20% lard fat, fructose 17.5%, 20% powdered rat food, 2.5% salt mixture, 5% water) provided similar results to previous studies . Ironically, the combination of high carbohydrate and high fiber is reported to confer hypolipidemic and hypoglycemic effects. In clinical studies, a high-carbohydrate and high-fiber diet is recommended as a diet therapy for diabetic patients because this diet can reduce postprandial blood sugar, insulin response, cholesterol and triglyceride levels. Therefore, the composition and combination of a high-carbohydrate diet are important factors that must be considered for inducing metabolic syndrome.

　　Fructose-rich diet: Fructose, commonly known as fruit sugar, is one of the monosaccharides of glucose and galactose. Nowadays, fructose is often used as a flavor enhancer to make food more delicious and attractive. Dietary fructose has no biological needs, it is just an intermediate molecule in the process of sugar metabolism. Compared with glucose, the circulating fructose concentration in peripheral blood is very low. Interestingly, a small amount of fructose replaces sucrose and starch in the diet of diabetic patients to produce a hypoglycemic response. Unfortunately, due to the consumption of artificially sweetened beverages and foods, too much fructose is consumed now. Theoretically, a large amount of fructose entering the liver leads to the accumulation of triglycerides and cholesterol due to its fat (lipogenic) properties, which subsequently leads to decreased insulin sensitivity, insulin resistance and glucose tolerance. The consumption of fructose leads to a large intake of fructose in the liver. Fructose is converted to fructose-1-phosphate. Fructose involves multiple processes: (a) a part of fructose is converted into lactic acid and pyruvate, (b) the other part produces triose phosphate, which is easily converted into glucose or glycogen, and (c) the char from fructose can be converted into Fatty acids, and (D) lipid peroxidation inhibition by fructose liver is beneficial to low-density lipoprotein (VLDL)-triglyceride synthesis and fatty acid esterification. As a result, this refined carbohydrate is quickly 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 feeding compared with glucose or starch in inducing metabolic syndrome in animal models. Previous studies have shown that glucose or starch feeding is not effective if sugar feeding induces metabolic syndrome. In addition, the mice fed fructose weighed more than the mice fed the same calories with starch. Long-term intake of high fructose and energy intake, body weight, obesity, hypertriglyceridemia, hyperlipidemia, hypertension, impaired glucose tolerance and reduced insulin sensitivity in experimental animals can all lead to metabolic syndrome. Studies have shown that rats fed a fructose-rich diet have elevated blood pressure, glucose intolerance, and decreased insulin sensitivity, accounting for 60% of total calories. There are also studies claiming that adding 10% fructose to drinking water and feeding high-dose fructose (60% of the diet) have the same effect in inducing hypertension and hyperlipidemia in male SD rats, but it is not as serious as high-dose fructose. . In short, fructose is more like fat than carbohydrate in humans and animals. Low-dose fructose (10%) in drinking water is sufficient to induce metabolic syndrome in animals.

　　High sucrose diet: It consists of a fructose molecule and a glucose molecule. Sucrose and fructose have the same effect, making food more palatable. Sucrase can break it down into its constituent components, namely glucose and fructose. Both of these molecules are absorbed by their special transport mechanism. As mentioned earlier, the uptake of glucose in glucose metabolism is negatively regulated by phosphofructokinase, which causes fructose to continuously join the glycolytic pathway. Excessive fructose will be converted into fat in the liver, because fructose is a good substrate for fatty acid synthesis. Therefore, fructose is the main active ingredient, which helps animals develop metabolic syndrome after sucrose consumption. Animal experiments show that adding 30% sucrose in drinking water can increase the body weight, systolic blood pressure, insulin, triglycerides, total cholesterol, low-density cholesterol (LDL) and free fatty acids in male Wistar rats and cause metabolic syndrome. 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 added to drinking water showed hyperglycemia, hypertriglyceridemia, hypercholesterolemia and weight gain. Rats supplemented with sucrose (77%), systolic blood pressure, plasma insulin and triglycerides increased significantly. Studies by Kasim Karakas et al. showed that golden hamsters fed only fructose had increased levels of fasting non-esterified fatty acids and triglycerides in plasma and liver. In addition, glucose tolerance was impaired, body weight and body fat increased significantly. Only fructose-fed (15%) rats were detected, but not in the other groups fed soft drinks (10% sucrose) and diet soft drinks (without calories). Fructose and sucrose feeding have different responses in two different animal models, namely SD and spontaneously hypertensive rats, which represent environmental and genetically acquired metabolic syndromes, respectively. Hyperfructoseemia causes hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, hypertension, and insulin resistance. At the same time, the concentration of sucrose in spontaneously hypertensive rats only increased blood pressure and increased insulin resistance. These previous findings indicate that high sucrose content is the key to the success of the metabolic syndrome animal model. However, fructose seems to be superior to an equivalent amount of sucrose in inducing metabolic syndrome, because fructose exists as a free molecule, while sucrose contains only 50% fructose and 50% glucose.

　　Fat-rich diet: Fat, also known as triglyceride, is an ester composed of three fatty acid chains and glycerol. Fat metabolism begins with the process of lipolysis. A large amount of glycerin and fatty acids diffuse freely into the blood. Plasma free fatty acids are the main substrate of liver VLDL triglycerides. Approximately 70% of the free fatty acids released will be re-esterified to form triglycerides (lipogenesis). The rate of re-esterification depends on the production rate of fatty acid glycerol-3-phosphate by glycolysis and release from fat cells. Free and re-coupling action esterified fatty acids (triglycerides) to form very low-density lipoproteins, helping fats circulate in the blood in water-based solutions. Many researchers use different types of high-fat diets, varying between 20 to 60% of total energy. The source of the fat component may be vegetable oil (such as corn, safflower or olive oil) or animal fat (such as beef tallow and lard). High-fat feed has been widely used in the metabolic syndrome of experimental animals. More specifically, high-fat diets are widely used to induce obesity in animals. Studies have also shown that a high-fat diet helps promote blood sugar, insulin resistance, dyslipidemia and the increase of free fatty acids in the blood. The purpose of the study by Ghibaudi et al. was to explore the long-term effects of dietary fat with different fat content (10, 32 and 45%) on obesity and metabolism in rats. The results of the study showed that the levels of energy intake, weight gain, fat mass, blood sugar, cholesterol, triglycerides, free fatty acids, leptin and insulin increased in a dose-dependent manner with the increase of 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. Later investigations found that high fat intake increased the body weight, total cholesterol and leptin levels of male C57BL/6 mice. Another recent study showed that mice fed a high-fat diet had increased body weight, blood lipids, plasma insulin and insulin resistance compared with mice fed a standard diet. The increased formation of very low-density lipoprotein helps to assemble triglycerides from a high-fat diet that leads to liver synthesis. High levels of very low-density lipoprotein cholesterol can lead to obesity, dyslipidemia, and cholesterol accumulation in arteries. The accumulation of triglycerides in the liver can cause insulin resistance.

　　Genetic model of metabolic syndrome: In addition to diet-induced metabolic syndrome animal models, in order to study the pathogenesis of metabolic syndrome caused by genetic factors, genetic animal models must be established. These genetic models of metabolic syndrome are time-saving because the development time of metabolic syndrome is significantly shorter than 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, such as leptin-deficient mice (ob/ob), leptin receptor-deficient mice (db/db), (ZF) rats, and diabetic fat (ZDF) rats. Leptin, as an anti-obesity hormone that binds to the leptin receptor, is secreted by mature adipocytes and is proportional to the size of the fat depot. Circulating leptin is taken into the hypothalamus to reduce food intake and appetite, and increase energy consumption through multiple signaling pathways. Therefore, the occurrence of obesity in these models is mainly due to abnormal leptin signaling, which leads to bulimia (food cravings) and reduces energy expenditure. Leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice are autosomal recessive mutation models of leptin gene (chromosome 6) and leptin receptor gene (chromosome 4), respectively. Leptin deficiency (ob/ob) mice develop obesity, hyperinsulinemia and hyperglycemia without hypertension and dyslipidemia. Both hypertension and dyslipidemia did not develop after 38 weeks. The leptin receptor-deficient (db/db) mice developed obesity, hyperglycemia, and dyslipidemia without hypertension. (GK) The animal model of rat leptin resistance is considered to be the best non-obese type 2 diabetes model. They spontaneously develop hyperleptinemia, hyperglycemia, reduce appetite, beta cell function, increase gluconeogenesis, and visceral fat accumulation. Among all these leptin and leptin receptor-related animal models, ZF rats, ZDF rats, and DS/obese rats are suitable models because these rats exhibit all the conditions of metabolic syndrome.

　　Drug/chemically induced metabolic syndrome model: Glucocorticoid-induced metabolic syndrome: Endogenous glucocorticoids are natural stress hormones secreted by the adrenal glands. Exogenous glucocorticoids are used to treat a variety of human diseases, such as autoimmune diseases and cancer. It can also be used to prevent rejection in organ transplants. However, glucocorticoid therapy can bring undesirable side effects, such as weight gain, glucose intolerance, impaired calcium homeostasis, osteoporosis, cataracts, and central nervous system effects. In animal models, endogenous and exogenous glucocorticoids are used to develop metabolic syndrome. The metabolic syndrome caused by glucocorticoids directly acts on different tissues and organs (such as liver, muscle, fat, and kidney) through several mechanisms: (1) Glucocorticoids promote the differentiation of pre-adipocytes into mature adipocytes; ( 2) Glucocorticoids can increase lipolysis and release free fatty acids; (3) Glucocorticoids can increase muscles and increase free amino acid hydrolysis. Amino acids induce the activation of mammalian target of rapamycin complex (mTORC1) and lead to the phosphorylation of insulin receptor substrate (IRS-1), leading to the occurrence of insulin resistance; (4) Glucocorticoids promote liver and cause hyperglycemia And gluconeogenesis; (5) non-specific binding of glucocorticoids and their receptors causes sodium retention in the kidneys, increases potassium excretion, water retention, and plasma volume accompanied by increased blood pressure. Using experimental animals, glucocorticoid-induced metabolic syndrome has been accomplished through various means, such as feeding, daily intraperitoneal injection of glucocorticoid, or surgical implantation of pellets. All these different routes of glucocorticoid administration have led to almost the same results. Corticosterone levels increase the animal's food intake, weight gain, abdominal fat accumulation, severe fasting hyperglycemia, Insulin resistance, impaired glucose tolerance, high blood pressure, dyslipidemia, and lipid deposition in visceral fat, liver tissue and skeletal muscle.

　　 Metabolic syndrome caused by antipsychotic drugs: Antipsychotic drugs are drugs used to treat neuropsychiatric diseases, such as schizophrenia, depression, and bipolar disorder. Antipsychotic drugs are associated with a high incidence of metabolic syndrome, 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. Olanzapine, the second-generation antipsychotic drug, is injected intraperitoneally or orally into rats and mice, interacting with the intestinal flora, resulting in weight gain, increased plasma free fatty acids, infiltration of adipose tissue macrophages, and visceral fat deposition. Since antipsychotic drugs are important drugs for the treatment of mental illnesses, continuous research is needed to clarify the possible mechanism of the metabolic syndrome induced by antipsychotics, so as to avoid such side effects.

　　 Conclusion: In short, the advantage of using animal models to study metabolic syndrome is that it can monitor the histological, functional, biochemical and morphological changes of metabolic syndrome, which is difficult to perform in humans. In addition to its pathophysiological similarity with human metabolic syndrome, excellent animal models should also be reproducible, simple, reliable and with minimal disadvantages.