The role of hypothalamic PPARg in diet-induced obesity

下丘脑 PPARg 在饮食引起的肥胖中的作用

• 批准号: 7998207
• 负责人: Karen Ryan
• 金额: $ 5.22万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7998207
• 关键词: Acute; Adipose tissue; Adult; Adverse effects; Affinity; Agonist; Binding; Body Weight; Body fat; Cardiovascular Diseases; Centers for Disease Control and Prevention (U.S.); Chronic; Clinical; Complement; Consumption; Data; Diabetes Mellitus; Diet; Diet Habits; Dietary Fats; Disease; Drug Prescriptions; Eating; Environment; Epidemic; Etiology; Exposure to; Fatty acid glycerol esters; Food; Gene Expression; Genetic Transcription; Glucose; Guidelines; Homeostasis; Hyperphagia; Hypothalamic structure; Incidence; Injection of therapeutic agent; Intervention; Knockout Mice; Knowledge; Laboratory Rat; Lentivirus Vector; Leptin; Leptin resistance; Ligands; Light; Link; Lipids; Liver; Malignant Neoplasms; Measures; Melanocortin 4 Receptor; Metabolic; Metabolic syndrome; Modeling; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Nutritional; Obesity; Obesity associated disease; Overweight; POMC gene; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Physiology; Play; Population; Process; Public Health; Rattus; Receptor Activation; Regulation; Relative (related person); Reporting; Research; Risk Factors; Role; Signal Transduction; Skeletal Muscle; Structure of nucleus infundibularis hypothalami; Symptoms; System; Testing; Therapeutic; Tissues; Training; United States; Weight Gain; Work; blood glucose regulation; career; cost; energy balance; feeding; glucose metabolism; insulin sensitizing drugs; lipid metabolism; obesogenic; public health relevance; research study; response; rosiglitazone; sensor; small hairpin RNA; statistics; transcription factor; trend

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.

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，过去 20 年来，美国成年人肥胖人数翻了一番，目前近 2/3 的成年人口超重或肥胖。鉴于肥胖是癌症、心血管疾病和糖尿病等许多其他疾病的危险因素，这些统计数据对公共健康的影响是惊人的。这种持续的流行病是生理学与日益导致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，被脂质激活，诱导脂质和葡萄糖代谢相关基因的表达，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，并且下丘脑在葡萄糖和脂质稳态的中枢调节中发挥重要作用，但实际上对下丘脑 PPARg 的功能一无所知。该提案将检验以下总体假设：中枢 PPARg 调节能量平衡，这可能是膳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总体假设。具体目标 1：检验中枢 PPARg 的生理和药物激动剂激活促进正能量平衡的假设。具体目标 2：检验 CMS PPARg 激活通过减少 MC4 受体激活促进正能量平衡的假设。具体目标 3：检验以下假设：CMS PPARg 的激活是高脂饮食诱导的瘦素抵抗和肥胖的关键部分。对这些假设的检验需要在各种饮食模型和 MC4 敲除小鼠中进行 CNS PPARg 的急性药理学抑制或激活实验，并通过将带有慢病毒载体的短发夹 RNA 注射到弓状体中来慢性减少 PPARg 表达的实验作为补充。下丘脑核。公共健康相关性：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相关的途径。这一贡献意义重大，因为它有望提供以下方面所需的知识：1）开发药物干预措施来调节该途径和/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。