Obesity is a Surgical Problem

肥胖是一个外科问题

基本信息

批准号：
8066467
负责人：
MICHAEL W. MULHOLLAND
金额：
$ 33.52万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-08-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8066467
关键词：
American Animal Model Ankyrin Repeat Area Basic Science Binding Body Weight Boxing Brain Cardiovascular Diseases Cholelithiasis Complex Cyclic AMP Degenerative polyarthritis Desire for food Diet Disease Eating Energy Metabolism Epidemic Fatty acid glycerol esters Feeding behaviors Gastric Bypass Gene Expression Genes Glucose Health Homeostasis Hypothalamic structure Insulin Receptor Investigation JUN gene Ligands Lung diseases Mediating Messenger RNA Mitogen-Activated Protein Kinases Modeling Morbid Obesity Morbidity - disease rate Neurons Non-Insulin-Dependent Diabetes Mellitus Obesity Operative Surgical Procedures Overweight Peptides Physiology Post-Transcriptional Regulation Postoperative Period Pro-Opiomelanocortin Process Proteins Receptor Signaling Regulation Research Resistance Role Satiation Series Signal Pathway Signal Transduction Societies Structure of nucleus infundibularis hypothalami Surgeon System Testing Transcriptional Regulation Transgenic Animals alpha-Melanocyte stimulating hormone anorexigenic peptide cancer type drug development energy balance experience genetic regulatory protein glucose metabolism in vivo insight melanocortin receptor mortality mutant obesity treatment overexpression receptor research and development research study stress-activated protein kinase 1

项目摘要

DESCRIPTION (provided by applicant): American society is experiencing an epidemic of obesity. Because of the key role of the hypothalamus in controlling body weight, the long-term objective of this research has been to examine arcuate nucleus hypothalamic genes involved in energy homeostasis. The proposed studies focus upon the hypothalamic melanocortinergic system which has become a focal point for basic research and drug development. That system contains alpha melanocyte-stimulating hormone (1-MSH) and melanocortin receptor (MCR) subtypes MC3R and MC4R. 1-MSH is a potent satiety-inducing factor that mediates its effects by binding and activating MC3R and MC4R. A continuing analysis of hypothalamic gene expression changes has identified ankyrin repeat and SOCS box containing protein 4 (Asb-4) as a very promising investigative target. Asb-4 is an important intracellular regulatory protein in CNS energy homeostatic circuits that is highly regulated in hypothalamic neurons. The proposed research is contained in four specific aims: 1) To examine alternative melanocortin signaling pathways. We hypothesize that MC3R and MC4R activate mitogen-activated protein kinase signaling pathways in addition to well- recognized cyclic AMP-dependent processes in hypothalamic neurons. 2) To determine the role of melanocortin signaling in regulation of c-Jun NH2-terminal kinase (JNK). We hypothesize that MC3R and MC4R, via Asb-4, regulate arcuate nucleus JNK activity. 3) To elucidate transcriptional regulation of Asb-4. We hypothesize that Asb-4 expression in the hypothalamus is regulated by the melanocortinergic peptide, 1-MSH. 4) To determine the role Asb-4 in feeding behavior. We hypothesize that ankyrin repeat and SOCS box containing protein 4 is a crucial intracellular protein in hypothalamic neurons. We hypothesize that directed overexpression of Asb-4 in hypothalamic proopiomelanocortin neurons will decrease food intake, increase energy expenditure and confe resistance to high fat diet-induced obesity. PUBLIC HEALTH RELEVANCE: American Society is experiencing an epidemic of obesity. The hypothalamis, an area in the brain that is essential in control of appetite and food intake, is the focus of these investigations. The proposal examines carefully the hypothalamic melanocortin signaling system, an important energy regulatory system that has postulated to effect appetite, energy expenditure, and glucose metabolism.

描述（由申请人提供）：美国社会正在经历肥胖流行病。由于下丘脑在控制体重方面发挥着关键作用，本研究的长期目标是检查下丘脑弓状核与能量稳态有关的基因。拟议的研究重点是下丘脑黑皮质能系统，该系统已成为基础研究和药物开发的焦点。该系统包含 α 黑素细胞刺激激素 (1-MSH) 和黑皮质素受体 (MCR) 亚型 MC3R 和 MC4R。 1-MSH 是一种有效的饱腹感诱导因子，通过结合和激活 MC3R 和 MC4R 来介导其作用。对下丘脑基因表达变化的持续分析已确定锚蛋白重复序列和含有蛋白 4 (Asb-4) 的 SOCS 盒是非常有前途的研究靶点。 Asb-4 是中枢神经系统能量稳态回路中重要的细胞内调节蛋白，在下丘脑神经元中受到高度调节。拟议的研究包含四个具体目标：1）检查替代黑皮质素信号通路。我们假设 MC3R 和 MC4R 除了在下丘脑神经元中众所周知的环 AMP 依赖性过程外，还激活丝裂原激活的蛋白激酶信号传导途径。 2) 确定黑皮质素信号传导在 c-Jun NH2 末端激酶 (JNK) 调节中的作用。我们假设 MC3R 和 MC4R 通过 Asb-4 调节弓状核 JNK 活性。 3) 阐明Asb-4的转录调控。我们假设下丘脑中的 Asb-4 表达受到黑皮质素能肽 1-MSH 的调节。 4) 确定Asb-4在摄食行为中的作用。我们假设含有蛋白 4 的锚蛋白重复序列和 SOCS 盒是下丘脑神经元中至关重要的细胞内蛋白。我们假设下丘脑阿黑皮质素原神经元中 Asb-4 的定向过度表达将减少食物摄入、增加能量消耗并增强对高脂肪饮食引起的肥胖的抵抗力。公共卫生相关性：美国社会正在经历肥胖流行病。下丘脑是大脑中对于控制食欲和食物摄入至关重要的区域，是这些研究的重点。该提案仔细检查了下丘脑黑皮质素信号系统，这是一种重要的能量调节系统，被认为会影响食欲、能量消耗和葡萄糖代谢。