Role of hypothalamic PPAR-gamma in the control of food intake and body weight

描述(申请人提供)：激活核受体PPARy的化合物通过其强大的胰岛素增敏作用在治疗2型糖尿病中有效。尽管噻唑烷二酮(TZD)类合成PPARy激动剂有令人印象深刻的好处，但它也会导致体重增加和脂肪堆积。虽然这种体重增加通常归因于PPARy激活促进脂肪细胞分化和脂肪储存的效果，但研究证实，TZDS导致啮齿动物吞噬功能亢进，这种食物消耗的增加在很大程度上解释了这些药物导致的体重增加。在人类身上的报告也表明，TZD会增加饥饿。在这里，我们研究了PPAR？激动剂至少部分是通过中枢神经系统(CNS)机制介导的，神经元PPARy激活刺激大脑中的摄食中心。扩展这一假设，我们还提出，PPARy在促进正常摄食方面起着生理作用，因此，通过该受体减少的神经元信号将促进体重减轻和防止病理性体重增加。我们的策略有四个方面：1)表征PPARy在大脑中调节摄食的特定区域的分布；2)确定全身应用TZD是否通过激活啮齿动物模型中中枢神经系统的PPARy导致体重增加；3)确定PPARy介导的摄食背后的细胞机制；以及4)确定中央给药PPARy拮抗剂是否减少食物摄入量和体重。PPARy在啮齿动物体内的中枢神经系统表达分布将通过免疫染色和原位杂交进行定位。为了选择性地调节大脑中的PPARy活动，PPARy配体将通过脑管以低剂量传递给老鼠，并将监测对食物摄入量的影响。将对离散的与摄食相关的大脑区域进行生化分析，以确定注入PPARy配体(包括中枢和全身)是否对PPARy活性和与控制食物摄入量有关的细胞通路产生可测量的影响。这些研究调查了一种新的假说，该假说对2型糖尿病的治疗和体重调节都具有很高的潜在重要性。因此，这些实验的结果可能会导致开发治疗肥胖症和2型糖尿病的新药物疗法。 与公共健康相关：这些研究调查了一种控制脂肪生长和血糖水平的因素是否可以通过其在大脑中的作用来调节喂养行为和体重。这项研究将进一步加深我们对控制体重增加、食欲和血糖水平的分子途径的理解，并可能导致肥胖症和糖尿病的新疗法的开发。

DESCRIPTION (provided by applicant): Compounds that activate the nuclear receptor PPARy are effective in the treatment of type 2 diabetes through their potent insulin sensitizing effects. Despite their impressive benefits, the thiazoladinedione (TZD) class of synthetic PPARy agonists also cause weight gain and fat accumulation. Although this weight gain is often attributed to the effect of PPARy activation to promote adipocyte differentiation and lipid storage, studies have confirmed that TZDs induce hyperphagia in rodents and that this increase in food consumption largely accounts for weight gain induced by these drugs. Reports in humans also suggest that TZDs increase hunger. Here, we investigate the hypothesis that weight gain induced by PPAR? agonists is mediated, at least in part, through a central nervous system (CNS) mechanism whereby neuronal PPARy activation stimulates feeding centers in the brain. Extending this hypothesis, we also propose that PPARy plays a physiological role to promote normal feeding and, consequently, that reduced neuronal signaling via this receptor will promote weight loss and protect against pathological weight gain. Our strategy is four fold: 1) to characterize the distribution of PPARy in specific areas of the brain that regulate feeding, 2) to determine if systemic TZD administration causes weight gain via activation of PPARy in the CNS in rodent models, 3) to identify cellular mechanisms that underlie PPARy mediated feeding, and 4) to determine if central administration of PPARy antagonists reduces food intake and body weight. The CNS expression distribution of PPARy will be mapped by immunostaining and in-situ hybridization in rodents. To selectively modulate PPARy activity in the brain, PPARy ligands will be delivered at low doses to rats through a cerebral cannula and the effects on food intake will be monitored. Biochemical analysis will be performed on discrete feeding-relevant brain areas to determine if infusion of PPARy ligands (both centrally and systemically) has measurable effects on PPARy activity and on cellular pathways implicated in the control of food intake. These studies investigate a novel hypothesis of high potential importance to both the treatment of type 2 diabetes and the regulation of body weight. Accordingly, the outcome of these experiments could lead to the development of novel drug therapies for the treatment of obesity and type 2 diabetes. PUBLIC HEALTH RELEVANCE: These studies investigate whether a factor which controls fat growth and blood sugar levels can regulate feeding behavior and body weight through its actions in the brain. This research will further our understanding of the molecular pathways which control weight gain, appetite, and blood sugar levels, and may lead to the development of new treatments for obesity and diabetes.