The role of hypothalamic PPARg in diet-induced obesity

描述（由申请人提供）：根据疾病控制中心最近的一份报告，美国肥胖成年人的数量在过去20年中翻了一番，近2/3的成年人现在超重或肥胖。鉴于肥胖是许多其他疾病的风险因素，包括癌症，心血管疾病和糖尿病，这些统计数据的公共卫生影响是惊人的。这种持续的流行病是生理学和日益肥胖的环境之间相互作用的结果，包括无处不在的低成本高脂肪食物。PPARg是一种转录因子，其被脂质激活以诱导参与脂质和葡萄糖代谢的基因的表达，从而将营养信号转化为肝脏、肌肉和白色脂肪组织中的代谢反应。尽管PPARg也在下丘脑中表达，并且尽管下丘脑在葡萄糖和脂质稳态的中枢调节中起重要作用，但实际上对下丘脑PPARg的功能一无所知。这项建议将测试的总体假设，中央PPARg调节能量平衡，这可能是一个重要的机制，通过饮食脂肪的消费有助于肥胖。我们计划通过追求三个具体目标来检验总体假设。具体目标1：为了检验通过其生理和药物激动剂激活中央PPARg促进正能量平衡的假设。具体目的2：检验CMS PPARg活化通过减少MC 4受体活化促进正能量平衡的假设。具体目的3：检验CMS PPARg的活化是高脂饮食诱导的瘦素抵抗和肥胖的关键部分的假设。这些假设的测试将需要在各种饮食模型和MC 4敲除小鼠中使用CNS PPARg的急性药理学抑制或激活的实验，通过将具有慢病毒载体的短发夹RNA注射到下丘脑弓状核中来使用PPARg表达的慢性减少的实验来补充。公共卫生相关性：拟议研究的预期贡献是描述一种直接将膳食脂肪与暴饮暴食和体脂增加联系起来的途径。这一贡献是重要的，因为它有望提供以下所需的知识：1）开发药理学干预以调节该途径和/或2）开发适当的饮食指南以减轻肥胖和肥胖相关疾病日益增长的公共卫生负担。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.