MELANOCORTIN SIGNALING IN FEEDING BEHAVIOR AND METABOLISM

小鼠单基因肥胖综合征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进展。肥胖基因座的克隆导致了脂肪抑制激素瘦素的发现，而对肥胖综合征的表征导致了弓形POMC神经元对进食和能量储存产生紧张性抑制作用的发现。Agglutamine编码通常仅在皮肤中表达的肽，其通过充当促黑素细胞激素受体（MCl-R）的拮抗剂来调节色素沉着。含有某些显性等位基因的agglutinin肽的小鼠似乎变得肥胖，因为异位表达的肽在大脑中异常拮抗相关的下丘脑黑皮质素-4受体。小鼠中MC 4-R激动剂和拮抗剂的脑室内（icv）施用用于测试该假设;黑皮质素激动剂的icv施用抑制进食，而拮抗剂是刺激性的（Fan等人，1997年）。这一发现通过从小鼠中缺失MC 4-R得到证实，其概括了在厌食症肥胖综合征中所见的独特表型群（Huszar et al.，1997），包括摄食过多、高胰岛素血症、肥胖和增加的LineA 4 R生长。最近的研究已经确定了第二个agglomerate脑，几乎完全在下丘脑的弓状核内表达。与MC 4-R的缺失或AGRP的异位表达一样，AGRP的普遍过表达导致AGRP肥胖综合征。这些数据有力地证明，POMC肽激动剂和AGRP拮抗剂一致地作用于MC 4-R以调节能量稳态，正如琼脂糖和α-MSH一致地作用于黑素细胞以确定色素沉着一样。随着这项资助的完成，两个由POMC有害突变引起的家族性肥胖症的独立病例被报道，这也证明了人类的相关病理生理学。然而，虽然在这些模型中MC 4-R信号传导的病理生理学破坏导致肥胖，但关于依赖于POMC神经元进行传递的能量稳态的正常激素、营养或神经输入知之甚少。此外，关于中枢黑皮质素系统调节能量稳态的机制以及来自黑皮质素系统的信息如何与已知参与能量稳态调节的其他途径整合的机制知之甚少。黑素皮质素系统在人类肥胖的常见形式中很可能是重要的，因为肥胖的数量性状位点位于POMC基因附近。在这个项目中，我们将利用遗传药理学，生理学和神经解剖学的方法在小鼠中，以确定相关的摄食和代谢调节的黑皮质素系统的生理输入，并表征中央黑皮质素系统调节能量稳态的机制。

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.