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。肥胖位点的克隆导致了脂肪激素瘦素的发现，而弓形POMC神经元的表征导致了针刺肥胖综合征的发现，对摄食和能量储存发挥强直抑制作用。Agouti编码一种通常仅在皮肤中表达的肽，该肽通过作为黑素细胞刺激激素受体（MCl-R）的拮抗剂来调节色素沉着。含有agouti肽的某些显性等位基因的小鼠似乎会变得肥胖，因为该肽在大脑中的异位表达异常地拮抗相关的下丘脑黑素皮质素-4受体。采用小鼠脑室内（icv）给药MC4-R激动剂和拮抗剂来检验这一假设；静脉注射黑素皮质素激动剂会抑制进食，而拮抗剂则有刺激作用（Fan et al., 1997）。这一发现被小鼠MC4-R的缺失所证实，重现了阿古提肥胖综合征中所见的独特表型（Huszar等人，1997），包括贪食、高胰岛素血症、肥胖和linea4r生长增加。最近的研究已经确定了第二个刺鼠脑，几乎完全在下丘脑的弓形核内表达。与MC4-R缺失或豚鼠异位表达一样，AGRP普遍过表达导致豚鼠肥胖综合征。这些数据有力地证明，POMC肽激动剂和AGRP拮抗剂协同作用于MC4-R调节能量稳态，就像agouti和α - msh协同作用于黑素细胞决定色素沉着一样。随着这项拨款的完成，两例由POMC有害突变引起的家族性肥胖的独立病例被报道，证明了人类的相关病理生理。然而，尽管这些模型中MC4-R信号的病理生理破坏导致肥胖，但对于依赖POMC神经元传递的正常激素、营养或神经输入对能量稳态的影响知之甚少。此外，关于中央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已知参与能量稳态调节的其他途径整合，我们知之甚少。由于肥胖的数量性状位点在POMC基因附近，黑素皮质素系统可能在人类肥胖的常见形式中很重要。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，在小鼠中确定与喂养和代谢调节相关的黑素皮质素系统的生理输入，并表征中央黑素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.