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

下丘脑 PPAR-γ 在控制食物摄入和体重中的作用

基本信息

批准号：
7780318
负责人：
David Alexander Sarruf
金额：
$ 5.38万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7780318
关键词：
5&apos -AMP-activated protein kinase Accounting Adipose tissue Adult Agonist Area Attention Biochemical Blood Glucose Body Weight Body Weight decreased Brain CISH gene Cannulas Cells Cerebrum Chromosomes Data Desire for food Development Diabetes Mellitus Dose Drug Delivery Systems Eating Ensure Epidemic Fatty acid glycerol esters Feeding behaviors Gene Expression Profiling Gene Targeting Genes Genetic Transcription Goals Growth Homeostasis Homologous Gene Human Hyperphagia Hypothalamic structure In Situ Hybridization Infusion procedures Innovative Therapy Insulin Intake Lateral Hypothalamic Area Lead Leptin Ligands Lipids Liver Maps Measurable Measures Mediating Messenger RNA Metabolic Diseases Mind Molecular Monitor Neuraxis Neuroglia Neurons Neuropeptides Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Obesity Outcome PPAR gamma Pathway interactions Patients Peptides Peripheral Peroxisome Proliferator-Activated Receptors Peroxisome Proliferators Pharmacotherapy Phosphoric Monoester Hydrolases Physiological Play Prevalence Pro-Opiomelanocortin Promoter Regions Protein Isoforms Proteins Rattus Regulation Relative (related person)Reporting Research Rodent Rodent Model Role Running Signal Transduction Staining method Stains Structure of nucleus infundibularis hypothalami Study Section Testing Tissues Transactivation Weight Gain Work activating transcription factor adipocyte differentiation cell type chromatin immunoprecipitation combat drug-induced weight gain energy balance feeding fighting food consumption human FABP4 protein immunoreactivity increased appetite lipoprotein lipase mRNA Expression melanin-concentrating hormone novel obesity treatment prevent public health relevance receptor research study response rosiglitazone tensin ventromedial hypothalamic nucleus

项目摘要

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.

描述（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敏化作用有效地治疗2型糖尿病。尽管具有令人印象深刻的益处，但合成par激动剂的噻唑烷二酮（TZD）类也会导致体重增加和脂肪积累。尽管这种体重增加通常归因于促进脂肪细胞分化和脂质储存的PPARY激活的影响，但研究证实，TZD会诱导啮齿动物的肥大，并且食品消耗的这种增加很大程度上说明了这些药物引起的体重增加。人类的报告还表明，TZD会增加饥饿感。在这里，我们研究了PPAR诱导的体重增加的假设？激动剂至少部分通过中枢神经系统（CNS）机制介导，神经元激活刺激大脑中的进食中心。扩展了这一假设，我们还建议PPARY起促进正常喂养的生理作用，因此，通过该受体减少神经元信号传导将促进体重减轻并预防病理体重增加。我们的策略是四个折叠：1）表征调节喂养的大脑特定区域的PPARY分布，2）确定系统性TZD给药是否会通过在啮齿动物模型中的CNS中激活PPARY而导致体重增加，3）识别PPARY介导的喂养的细胞机制，以及4）ppare Antoveration Antogagon Antogain Antoganist Fodains fodagonist Antoganist Intake and Redakeist和ReduceStive ReduceStive和4） PPARY的中枢神经系统表达分布将通过啮齿动物的免疫染色和原位杂交绘制。为了有选择地调节大脑中的PPARY活性，将通过脑套管以低剂量向大鼠递送PPARY配体，并将监测对食物摄入的影响。将对与离散喂养相关的大脑区域进行生化分析，以确定PPARY配体的输注（中央和系统上）是否对PPARY活性和与食物摄入控制有关的细胞途径具有可测量的影响。这些研究研究了对2型糖尿病治疗和体重调节的高潜在重要性的新假设。因此，这些实验的结果可能会导致肥胖症和2型糖尿病治疗的新型药物疗法的发展。公共卫生相关性：这些研究研究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喂养行为和体重。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的新治疗方法。