| Background Developed and developing countries are all confronted with the severe situation of increasing number of obesity. Obesity has become a worldwide epidemic, and it will become a severe health problem if not controlled efficiently. Now the anti-obesity agents on sale mainly have two species: one is appetite inhibitor which mainly works by acting on appetite control centers in the hypothalamus to decrease appetite, such as fenfluramine and sibutramine. However, food contains lots of necessary nutrient substances, long-term fasting will do great harm to human health. What's more, fenfluramine and dexfenfluramine can injure cardiac valves, which were forbidden by FDA in 1997. The plenty of adverse effects of Sibutramine such as mouth-drying, headache, palpitation and blood pressure elevation restricted its use as an anti-obesity agent. The other is inhibitor of dietary fat absorption, Orlistat, which inhibit lipase in intestinal tract to decrease lipid absorption. In view of using it for a long time could cause the deficiency of lipid-soluble vitamin, and increase the risk of colon carcinoma, American consumer organization requests to withdraw it from market.Many experts focus on exploitingβ3-AR(β3 adrenergic receptor)agonist as a anti-obesity agent now. Selectiveβ3-AR agonists can stimulateβ3-AR, promote lipid mobilization and make more energy produce heat. Especially high selectiveβ3-AR agonists can not only reduce body weight, but also have less adverse effects caused by stimulatingβ1 andβ2-AR. The related reports about animal anti-obesity experiments of betaphrine as a potentialβ3-AR agonist have not been seen at present.Objectives This study was initiated to investigate the anti-obesity effects of betaphrine in diet-reduced obesity rats (DIO), to explore its possible action mechanism of the weight loss effect and have a preliminary knowledge of its cardiovascular adverse effects. This study may provide a preliminary experimental basis for developing a new anti-obesity agent.MethodsChapter 1 Effect of betaphrine on diet-reduced obesity modelsDIO models were established by the just ablactating male and female Wistar rats fed high alimentary diet for 7 weeks, then the model rats were randomized into five groups by intragastric administration with sibutramine 4 mg/kg/d, betaphrine 10, 30, 90 mg/kg/d as the same volume as normal saline solution (NS) in control group and model group for 7 weeks, respectively. During the therapy, we measured body weight every week. All of the animals were sacrificed before measuring the weight of adipose tissue, the areas and numbers of adipocity, the level of blood glucose and serum lipid at the end of the experiment.Chapter 2 Effects of betaphrine on lipid-mobilizing and cardiovascular effects (in vivo) in ratsWe chose Wistar rats and randomized them into four groups, then administrated isoproterenol (ISO) 0.01 mg/kg/min, betaphrine 0.1, 1 mg/kg/min respectively by intravenous injection, as the same volume as normal saline solution (NS) in control group. After anesthetized by pentobarbital sodium, common carotid arteries of rats were separated and inserted with catheters linked with pressure transducer which was connected with detecting instrument; then femoral veins were separated and punctured directly by scalp acupunctures, from which the agents were infused and blood samples were obtained. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP) and heart rate (HR) were tested before and after infusion respectively, then blood samples and epididymal adipose tissue were obtained after 10 minutes terminating infusion for the measure of the concentration of the free fatty acid (FFA).ResultsAt the end of 7 weeks of establishing model, the body weight of the male rats in model group were higher than control group significantly (p<0.01), but that of the female rats had no significance (p>0.05). Betaphrine reduced body weight of obese male rats and body weight gain significantly, but it had on effects on body weight and body weight gain of female rats. In a dose-dependent manner, betaphrine decreased the weight of WAT and BAT of male and female rats. Betaphrine decreased the level of serum free fatty acid (FFA) of male and female rats significantly, but only decreased the level of blood glucose, serum triglyeride (TG) of male rats. Betaphrine decreased adipocyte areas and increased the numbers of adipocyte of male and female rats significantly.After 10 min infusion of betaphrine and isoproterenol, respectively, the level of serum and adipose tissue concentration of FFA were increased in all dose groups compared with those of control group; SBP,DBP,MAP and HR in low-dose group were not changed; but DBP and MAP in high-dose group were decreased significantly(p<0.05).ConclusionTreatments with betaphrine are effective on the body weight increasing rate of male DIO, but have no effects that of female rats with normal body weight. Betaphrine can decrease the weight of WAT and BAT and the level of serum FFA of male and female rats, but it can only decrease the level of blood glucose and serum TG of male rats. Betaphrine can increase the level of serum and adipose tissue concentration of FFA, which may hint that its possible mechanism of anti-obesity effect is promoting lipid mobilization and reducing the weight of adipose tissue. Betaphrine has little effects on blood pressure and HR, only high-dose group has cardiovascular adverse effects of decreasing DBP and MAP, so these advantages make it be an adapted target to use in clinic.
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