MELANOCORTIN SIGNALING IN FEEDING BEHAVIOR AND METABOLISM

进食行为和代谢中的黑皮质素信号传导

• 批准号: 6465781
• 负责人: Roger D. Cone
• 金额: $ 17.24万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6465781
• 关键词: adrenocorticotropic hormone; behavioral /social science research tag; bioenergetics; eating; genetic mapping; genetic regulation; hormone receptor; hormone regulation /control mechanism; hypothalamic hormones; laboratory mouse; melanocyte stimulating hormone; nutrition related tag; obesity; proopiomelanocortin

The discovery and characterization of single-gene obesity syndromes in the mouse has led to dramatic progress in our understanding of the neuroendocrine control of energy homeostasis. Cloning of the obesity locus led to the discovery of the adipostatic hormone, leptin, while characterization of the agouti obesity syndrome led to the finding that the arcuate POMC neurons exert a tonic inhibitory effect on feeding and energy storage. Agouti encodes a peptide normally expressed only in skin that regulates pigmentation by acting as an antagonist of the melanocyte- stimulating hormone receptor (MCl-R). Mice containing certain dominant alleles of the agouti peptide appear to become obese because ectopic expression of the peptide in the brain aberrantly antagonizes the related hypothalamic melanocortin-4 receptor. Intracerebroventricular (icv) administration of MC4-R agonists and antagonists in the mouse were used to test this hypothesis; icv administration of melanocortin agonists inhibited feeding, while an antagonist was stimulatory (Fan et al., 1997). This finding was corroborated by deletion of the MC4-R from the mouse, which recapitulated the unique constellation of phenotypes seen in the agouti obesity syndrome (Huszar et al., 1997), including hyperphagia, hyperinsulinemia, obesity, and increased linea4r growth. Recent studies have identified a second agouti brain, is expressed almost exclusively within the arcuate nucleus of the hypothalamus. Like deletion of the MC4-R or ectopic expression of agouti, ubiquitous over-expression of AGRP causes the agouti obesity syndrome. These data argue strongly that POMC peptide agonists and the AGRP antagonists act in concert on the MC4-R to regulate energy homeostasis just as agouti and alpha-MSH act in concert on the melanocyte to determine pigmentation. As this grant was being completed, two independent cases of familial obesity resulting from deleterious mutations in POMC were reported, demonstrating related pathophysiology in humans as well. However, while pathophysiological disruption of MC4-R signaling causes obesity in these models, little is known regarding the normal hormonal, nutritional, or neural inputs to energy homeostasis that are dependent upon the POMC neurons for their transmission. Furthermore, little is known regarding the mechanisms by which the central melanocortin system regulates energy homeostasis and how information derived from the melanocortin system integrates with other pathways known to be involved in regulation of energy homeostasis. The melanocortin system may well be important in common forms of human obesity since a quantitative trait locus for obesity maps near the POMC gene. In this project we will utilize genetic pharmacological, physiological, and neuroanatomical approaches in the mouse to determine the physiological inputs to the melanocortin system relevant to the regulation of feeding and metabolism, and to characterize the mechanisms by which the central melanocortin system regulates energy homeostasis.

单基因肥胖综合征在小鼠中的发现和表征使我们对能量稳态的神经内分泌控制的理解取得了巨大的进步。肥胖基因的克隆导致了脂肪激素瘦素的发现，而对刺鼠肥胖综合征的描述则导致了弓状POMC神经元对摄食和能量储存的紧张性抑制作用。刺参编码一种通常只在皮肤中表达的多肽，通过作为黑素细胞刺激素受体(MCL-R)的拮抗剂来调节色素沉着。含有刺激肽的某些显性等位基因的小鼠似乎变得肥胖，因为这种多肽在大脑中的异位表达异常地拮抗了相关的下丘脑黑素皮质素-4受体。小鼠脑室注射MC4-R激动剂和拮抗剂来验证这一假说；脑室注射黑素皮质素激动剂抑制进食，而拮抗剂则是刺激性的(Fan等人，1997)。这一发现得到了小鼠MC4-R基因缺失的证实，该基因概括了在豚鼠肥胖综合征(Huszar等人，1997)中看到的独特的表型星座，包括吞噬功能亢进、高胰岛素血症、肥胖和直线生长增加。最近的研究发现了第二个刺鼠脑，几乎只在下丘脑的弓状核中表达。与MC4-R缺失或刺鼠蛋白异位表达一样，AGRP的普遍过度表达导致了刺鼠肥胖综合征。这些数据有力地证明了POMC多肽激动剂和AGRP拮抗剂协同作用于MC4-R来调节能量平衡，就像刺鼠和α-MSH协同作用于黑素细胞来确定色素沉着一样。随着这笔赠款的完成，有两个独立的家族性肥胖病例被报告，这些病例是由POMC有害突变引起的，也证明了人类的相关病理生理。然而，在这些模型中，虽然MC4-R信号的病理生理破坏导致肥胖，但关于依赖POMC神经元进行传递的正常激素、营养或神经输入到能量稳态的情况知之甚少。此外，关于中枢黑素皮质素系统调节能量稳态的机制，以及来自黑素皮质素系统的信息如何与其他已知的参与能量稳态调节的途径整合，人们知之甚少。黑素皮质素系统在常见的人类肥胖症中可能很重要，因为肥胖症的数量性状基因定位在POMC基因附近。在这个项目中，我们将利用小鼠的遗传药理学、生理学和神经解剖学方法来确定与摄食和代谢调节相关的黑素皮质素系统的生理输入，并表征中枢黑素皮质素系统调节能量稳态的机制。