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

说明（由申请人提供）：激活核受体PPARy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。尽管噻唑烷二酮（TZD）类的合成PPARy激动剂具有令人印象深刻的益处，但它们也引起体重增加和脂肪积累。尽管这种体重增加通常归因于PPARy活化促进脂肪细胞分化和脂质储存的作用，但研究已经证实TZD诱导啮齿动物的摄食量过多，并且这种食物消耗的增加在很大程度上解释了这些药物诱导的体重增加。人类的报告也表明TZD会增加饥饿感。在这里，我们调查的假设，体重增加引起的过氧化物酶体增殖物激活受体？激动剂至少部分地通过中枢神经系统（CNS）机制介导，由此神经元PPARy活化刺激脑中的摄食中心。扩展这一假设，我们还提出，PPARy发挥生理作用，以促进正常进食，因此，减少通过这种受体的神经元信号传导将促进体重减轻和防止病理性体重增加。我们的战略有四个方面：1）表征PPARy在调节进食的大脑特定区域中的分布，2）确定全身性TZD给药是否通过激活啮齿动物模型中的中枢神经系统中的PPARy导致体重增加，3）确定PPARy介导的进食的细胞机制，和4）确定PPARy拮抗剂的中央给药是否会减少食物摄入量和体重。将通过啮齿动物中的免疫染色和原位杂交绘制PPARy的CNS表达分布。为了选择性地调节脑中的PPARy活性，将通过脑插管将低剂量的PPARy配体递送至大鼠，并监测对食物摄入的影响。将对离散的进食相关脑区进行生化分析，以确定PPARy配体的输注（中枢和全身）是否对PPARy活性和涉及食物摄入控制的细胞途径具有可测量的影响。这些研究调查了一种对2型糖尿病的治疗和体重调节都具有潜在重要性的新假设。因此，这些实验的结果可能导致开发用于治疗肥胖和2型糖尿病的新型药物疗法。 公共卫生相关性：这些研究调查了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进食行为和体重。这项研究将进一步了解控制体重增加，食欲和血糖水平的分子途径，并可能导致肥胖和糖尿病新疗法的开发。

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.