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

描述（由申请人提供）：激活核受体pparty的化合物通过其有效的胰岛素增敏作用有效治疗2型糖尿病。尽管有令人印象深刻的好处，噻唑拉定二酮（TZD）类合成pparty激动剂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pparty激活促进脂肪细胞分化和脂质储存的作用，但研究已经证实，TZDs诱导啮齿动物嗜食，这种食物消耗的增加在很大程度上解释了这些药物引起的体重增加。对人类的研究报告也表明，tzd会增加饥饿感。在这里，我们研究了PPAR诱导体重增加的假设。激动剂至少部分通过中枢神经系统（CNS）机制介导，即神经元pparty激活刺激大脑中的摄食中枢。延伸这一假设，我们还提出pparty在促进正常摄食方面发挥生理作用，因此，通过该受体减少的神经元信号传导将促进体重减轻并防止病理性体重增加。我们的策略有四个方面：1)表征PPARy在调节摄食的大脑特定区域的分布；2)确定在啮齿动物模型中，全身给药TZD是否通过激活中枢神经系统中的PPARy导致体重增加；3)确定PPARy介导摄食的细胞机制；4)确定中央给药PPARy拮抗剂是否会减少食物摄入和体重。利用免疫染色和原位杂交技术绘制PPARy在啮齿动物中枢神经系统的表达分布。为了选择性地调节pparty在大脑中的活动，pparty配体将通过脑插管以低剂量输送给大鼠，并监测其对食物摄入的影响。生化分析将在与进食相关的离散脑区进行，以确定PPARy配体的输注（包括中枢和系统）是否对PPARy活性和与食物摄入控制有关的细胞通路有可测量的影响。这些研究探讨了一种对2型糖尿病的治疗和体重调节具有高度潜在重要性的新假设。因此，这些实验的结果可能会导致治疗肥胖和2型糖尿病的新型药物疗法的发展。

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.