动物造模,药效评价,诱发性肥胖 z-bio 2024-08-02 486

　　1. Dietary induced nutritional obesity rat and mouse models

　　The occurrence of obesity is the result of energy metabolism disorders in the body, and its exact pathogenesis is not fully understood. Currently, it is believed to be related to genetics, central nervous system abnormalities, endocrine dysfunction, metabolic factors, and nutritional imbalance, as well as closely related to environmental factors. Nutritional obesity is a type of obesity disease. At present, there have been numerous reports on diet induced obesity animal models. Among them, the diet induced obesity rat and mouse models provide calories from high-fat foods that exceed the needs of various metabolic processes in the body, causing excessive calories to be converted into fat accumulation and leading to obesity.

　　[Model making] Suitable for rat and mouse strains, feeding high-fat diet can lead to obesity. The most commonly used product in current literature reports is Research Diet's product. There is a detailed introduction on its company website, and the website link is http://www.researchdiets.com/opensouree-diets/diet-induced-disease-models/obesity .

　　【 Model Features 】 KK Ay, ob/ob, db/db mice, and Zucker rats are obesity models generated by single gene mutations in specific mouse backgrounds. There are few cases of similar mutations in human diseases. Diet induced obesity models in rats and mice are mainly caused by excessive calorie intake from high-fat foods, which is more similar to human obesity diseases.

　　When selecting rat and mouse strains, it is important to note that C57BL/6J mice and Sprague Dawley rats are considered good high-fat diet induced obesity models and are also the most commonly used. However, A/J mice, S5B/PI, and Lou/C rat strains are not suitable as animal models for high-fat diet induced obesity resistance.

　　2. Diet induced obesity model in miniature pigs

　　The modeling mechanism is similar to that of diet induced obese rat and mouse models.

　　[Model making] Adult 30-35kg G ö ttingen miniature pigs can freely consume normal pig feed, and the increase in food intake leads to weight gain in miniature pigs. By around 18 months, the weight of pigs that feed freely can reach 2-3 times that of pigs that are restricted in their diet.

　　【 Model Features 】 The successful modeling of obesity in 18 month old miniature pigs can achieve a body fat content of up to 50% of body weight, similar to human obesity caused by overeating due to strong appetite.

　　[Model evaluation and application scope] Although this model shows insulin resistance, it will not develop into type 2 diabetes. Similar to humans, the pathogenesis of this miniature pig model is not clear, so attention should be paid when using it.

　　3. Animal model of hypothalamic obesity

　　The hypothalamus is the appetite regulating center of the human body, which receives and integrates neuroendocrine factors produced by the central nervous system and peripheral tissues that promote or inhibit appetite. It precisely regulates body weight and appetite, maintaining weight stability. At the beginning of the 20th century, it was observed that hypothalamic injury (such as hypothalamic tumors, encephalitis, etc.) could cause obesity. 50 years later, Hetherington used electricity to damage the ventral medial area of the hypothalamus on both sides, successfully creating an obese rat model and truly pioneering research on hypothalamic obesity. The regions on both sides of the hypothalamus are related to feeding activity and hunger sensation, while the middle area of the inner abdomen is related to satiety and cessation of feeding activity. Damage to the central area of the hypothalamus or related areas can cause obesity. This type of obesity caused by changes in the hypothalamus is called hypothalamic obesity.

　　[Modeling Method] The study of hypothalamic obesity model specifically uses rodents, rats and mice, as experimental animals. Experimental hypothalamic obesity in rats or mice is mainly obtained through methods such as electrical damage to the ventromedial nucleus of the hypothalamus, surgical cutting of damaged fiber connections in the paraventricular nucleus, intraperitoneal injection of gold thioglucose (GTG), and subcutaneous injection of monosodium glutamate (MSG).

　　1. Electrical damage to the ventromedial nucleus of the hypothalamus

　　After intraperitoneal injection of 50mg/kg pentobarbital sodium anesthesia, the rats were fixed in a supine position. The head skin was disinfected with iodine and 75% ethanol, and the skull of the animal was carefully separated and exposed. The insertion coordinates of the electrolytic electrode were 6.2mm anterior to the midline of the ear, 0.6mm on both sides of the midline, and 9.6mm on the outer side of the anterior fontanelle. The current intensity reported abroad is 1-3mA, and the power on time is 10-30 seconds, with the most common being 2mA and 20 seconds.

　　2. GTG method: Dissolve 800mg/kg gold sulfur glucose in sesame oil or physiological saline, and inject once into the abdominal cavity of 6-8 week old male mice. On the 2nd to 4th day after injection, the food intake of the GTG treatment group was significantly lower than that of the control group. On the 8th to 20th day, the GTG treatment group showed increased appetite and significantly increased food intake. On the 13th day, the weight of the GTG treatment group began to be significantly higher than that of the control group.

　　3. MSG method: Healthy newborn rats or mice are divided into several litters (1-2 day old, with 8-10 mice per litter). 4-5 neonatal mice were subcutaneously injected with 3mg/kg MSG per day for 5 consecutive days, while the other neonatal mice were treated with physiological saline as a control group. 16% of injected neonatal mice will die, but 90% of surviving animals will significantly gain weight.

　　The prominent feature of the hypothalamic obese rats made by surgery is that they eat more, and their food intake can increase by 50% to 60%, or even more. Moreover, it has a unique "partial feeding" habit, which involves adding quinine or cellulose to feed, or feeding with powdered feed, significantly affecting food intake. In addition, it is often accompanied by hyperinsulinemia, hypertriglyceridemia, as well as abnormal aggressive and sexual behavior.

　　GTG causes damage to the ventromedial nucleus of the hypothalamus in rats or mice, leading to animal obesity. The insulin content in the blood and glucose absorption rate in the small intestine of GTG obese mice were significantly increased, while their food intake did not increase. groin

　　Fat pads, subcutaneous and thoracic fat in the pelvic and scapular regions, and significant increase in body weight.

　　MSG damages the arcuate nucleus of the hypothalamus in rats or mice, leading to significant obesity and an increase in Lee's index. Accumulation of a large amount of fat, reduced activity, decreased food intake, decreased metabolic rate, and decreased ability to respond to low-temperature stress. The levels of ACTH and indophenol in the brain decrease. The decrease of blood norepinephrine level and the weakening of sympathetic nervous system activity may be one of the basic factors causing high incidence rate and obesity. Elevated levels of luteinizing hormone in the blood of monosodium glutamate obese rats lead to skeletal and gonadal developmental disorders. Unlike the obesity model induced by GTG, the MSG induced model does not exhibit a phenotype of strong appetite.

　　There are several methods for creating animal models of hypothalamic obesity, each with its own characteristics. Therefore, the appropriate molding method should be selected based on the actual situation.

　　People can also develop hypothalamic obesity due to brain drooping tumors or cranial cavity injuries. Compared to simple obesity in humans, within a few days after the destruction of the hypothalamic ventromedial nucleus in animals, their appetite increases and they gradually become obese, leading to hyperinsulinemia, which is the cause of hypothalamic obesity. The causes of the two are different, but when compared from a pathological perspective, both have common manifestations such as abnormal appetite, endocrine hyperinsulinemia, low levels of growth hormone in the blood, and decreased gonadal function. Through the study of this model, it is helpful to study the causes and pathology of simple obesity in clinical practice.