The role of hypothalamic PPARg in diet-induced obesity

描述（由申请人提供）：根据美国疾病控制中心最近的一份报告，在过去的20年里，美国肥胖成年人的数量翻了一番，近三分之二的成年人现在超重或肥胖。鉴于肥胖是包括癌症、心血管疾病和糖尿病在内的许多其他疾病的风险因素，这些统计数据对公共卫生的影响是惊人的。这种持续的流行病是生理和日益肥胖的环境（包括无处不在的低成本高脂肪食物）之间相互作用的结果。PPARg是一种被脂质激活，诱导参与脂质和糖代谢的基因表达，从而将营养信号转化为肝脏、肌肉和白色脂肪组织的代谢反应的转录因子。尽管PPARg也在下丘脑中表达，尽管下丘脑在葡萄糖和脂质稳态的中枢调节中起着重要作用，但对下丘脑的PPARg功能几乎一无所知。这一提议将测试中枢PPARg调节能量平衡的整体假设，这可能是饮食脂肪消耗导致肥胖的重要机制。我们计划通过追求三个具体目标来检验整个假设。具体目的1：验证中枢PPARg通过其生理和药物激动剂激活促进正能量平衡的假设。具体目的2：验证CMS PPARg激活通过降低MC4受体激活促进正能量平衡的假设。具体目的3：验证CMS PPARg的激活是高脂饮食诱导瘦素抵抗和肥胖的关键部分的假设。要验证这些假设，需要在各种饮食模型和MC4基因敲除小鼠中使用急性药理抑制或激活中枢神经系统PPARg的实验，并通过向下丘脑弓状核注射带有慢病毒载体的短发夹RNA来慢性降低PPARg表达的实验。公共卫生相关性：拟议研究的预期贡献是描述膳食脂肪与暴饮暴食和体脂增加直接联系的途径。这一贡献是重要的，因为它有望提供所需的知识：1)开发调节这一途径的药理学干预和/或2)制定适当的饮食指南，以减轻肥胖和肥胖相关疾病日益增加的公共卫生负担。鉴于PPARg激动剂广泛用于治疗II型糖尿病，这项工作也有可能揭示这些药物引起体重增加的潜在机制。

DESCRIPTION (provided by applicant): According to a recent report from the Centers for Disease Control, the number of obese adults in the United States has doubled in the past 20 years and nearly 2/3 of the adult population is now overweight or obese. Given that obesity is a risk factor for numerous other diseases including cancer, cardiovascular disease and diabetes, the public health implications of these statistics are staggering. This ongoing epidemic results from an interaction between physiology and an increasingly obesigenic environment, including ubiquitous access to low-cost high-fat foods. PPARg is a transcription factor that is activated by lipids to induce the expression of genes involved in lipid and glucose metabolism, thereby converting nutritional signals into metabolic responses in liver, muscle and white adipose tissue. Although PPARg is also expressed in the hypothalamus, and although the hypothalamus plays an important role in the central regulation of glucose and lipid homeostasis, virtually nothing is known about the function of hypothalamic PPARg. This proposal will test the overall hypothesis that central PPARg modulates energy balance and that this may be an important mechanism by which consumption of dietary fats contributes to obesity. We plan to test the overall hypothesis by pursuing three specific aims. Specific Aim 1: To test the hypothesis that activation of central PPARg by its physiological and pharmaceutical agonists facilitates positive energy balance. Specific Aim 2: To test the hypothesis that CMS PPARg activation facilitates positive energy balance by reducing MC4 receptor activation. Specific Aim 3: To test the hypothesis that activation of CMS PPARg is a key part of high-fat diet-induced leptin resistance and obesity. Tests of these hypotheses will require experiments using acute pharmacological inhibition or activation of CNS PPARg in various dietary models and in MC4 knockout mice, complemented by experiments using chronic reduction in PPARg expression by injection of a short-hairpin RNA with a lentivirus vector into the arcuate nucleus of the hypothalamus. PUBLIC HEALTH RELEVANCE: The expected contribution of the proposed studies is to describe a pathway which directly links dietary fat to overeating and increased body fat. This contribution is significant because it is expected to provide the knowledge needed to 1) develop pharmacological interventions to modulate this pathway and/or 2) develop appropriate dietary guidelines to relieve the growing public health burden of obesity and obesity- related diseases. Given the wide use of PPARg agonists to treat type II diabetes, this work also has the potential to shed considerable light on underlying mechanisms of the weight gain caused by these drugs.