Melanocortin Signaling in Feeding Behavior

进食行为中的黑皮质素信号传导

• 批准号: 6890256
• 负责人: Roger D. Cone
• 金额: $ 29.84万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6890256
• 关键词: appetite regulatory center; bioenergetics; biological signal transduction; brain stem; cholecystokinin; dorsal motor nucleus; genetically modified animals; ghrelin; green fluorescent proteins; hormone receptor; hormone regulation /control mechanism; hunger; hypothalamus; immunofluorescence technique; laboratory mouse; neuroendocrine system; neuropeptide Y; neuroregulation; nutrient intake activity; nutrition related tag; pituitary hormones; proopiomelanocortin; satiations; solitary tract nucleus; stereotaxic techniques; stomach emptying; suid alphaherpesvirus 1; voltage /patch clamp

Obesity is a leading cause of morbidity and mortality as a risk factor for diabetes, cardiovascular disease, and cancer. The central melanocortin system is a critical circuit in the regulation of body weight and composition, with haploinsufficiency of the melanocortin-4 receptor (MC4-R) in humans the most common monogenic cause of severe obesity, accounting for up to 5% of cases. Consequently, a thorough understanding of the central melanocortin system will increase our understanding of obesity, improve differential diagnosis of obesity syndromes, and ultimately identify potential targets for drug development for the treatment of disorders of energy homeostasis. Much of the research in the field has been focused on the regulation of the arcuate proopiomelanocortin (POMC) neurons by leptin, and their role in mediating the long-term adipostatic leptin signal. Work from the first funding period of this grant also demonstrated an important role of the melanocortin system in satiety, and sensing of nutrient intake. Using an electrophysiological system developed in this laboratory for recording from arcuate POMC and NPY neurons, as well as neuroanatomical methods, we have discovered that these neurons not only respond to leptin, but are also regulated by acute hunger and satiety factors such as PYY3-36, insulin, CCK, and ghrelin. Likewise, in preliminary data provided here we show that MC4-R signaling also has an impact on gastric emptying, identifying a novel efferent pathway for regulation of satiety by this system. Indeed, data just published on MC4-R haploinsufficient humans documents a profound hyperphagia, and perhaps even binge eating in these individuals. These findings raise two intriguing hypotheses. First, most hunger and satiety signals are transmitted to the CNS via vagal afferents and humoral inputs to the brainstem. POMC is also expressed in a poorly characterized set of neurons in the nucleus of the solitary tract (NTS) in the brainstem, and the dorsal motor nucleus of the vagus, a key site of motor neurons regulating GI function, is a dense site of MC4-R expression. Thus, the central melanocortin system may be an important pathway for sensing and responding to hunger and satiety siqnals acting through vaqa! and humoral inputs to the brainstem melanocortin system, and perhaps, in the case of some humoral factors even acting directly on arcuate POMC neurons. Secondly, arcuate and brainstem POMC neurons send projections to a number of MC4-R-containing sites involved in autonomic outflow, like the PVN, DMH, IML, PBL, and DMV, and stereotaxic injection of melanocortJn compounds into the PVN can profoundly impact feeding behavior. Thus, the regulation of autonomic outflow to the gut by the melanocortin system may be an important pathway by which this system participates in the regulation of energy intake. In this next funding period, we will continue to characterize regulatory inputs to the central melanocortin system, and effector output pathways, with a focus on the role of the system in sensing and responding to acute hunger and satiety signals.

肥胖是糖尿病、心血管疾病和癌症发病率和死亡率的主要原因。中枢黑皮质素系统是调节体重和组成的关键回路，人类黑皮质素-4受体（MC 4-R）的单倍不足是严重肥胖症最常见的单基因原因，占病例的5%。因此，对中枢黑皮质素系统的深入了解将增加我们对肥胖的理解，改善肥胖综合征的鉴别诊断，并最终确定用于治疗能量稳态障碍的药物开发的潜在靶点。该领域的研究主要集中在瘦素对弓状前阿黑皮素（POMC）神经元的调节，以及它们在介导长期脂肪抑制性瘦素信号中的作用。这项资助的第一个资助期的工作也证明了黑皮质素系统在饱腹感和营养摄入感中的重要作用。使用 利用本实验室开发的用于记录弓状POMC和NPY神经元的电生理系统以及神经解剖学方法，我们发现这些神经元不仅对瘦素有反应，而且还受急性饥饿和饱足因子如PYY 3 -36、胰岛素、CCK和ghrelin的调节。同样，在这里提供的初步数据中，我们表明MC 4-R信号传导也对胃排空有影响，确定了一种新的传出途径， 这个系统对饱腹感的调节。事实上，刚刚发表的关于MC 4-R单倍不足人类的数据记录了这些人的严重暴食症，甚至可能是暴饮暴食。这些发现提出了两个有趣的假设。首先，大多数饥饿和饱足信号通过迷走神经传入和脑干的体液输入传递到中枢神经系统。POMC还在脑干中孤束核（NTS）中的一组特征不明显的神经元中表达，并且迷走神经背侧运动核（调节GI功能的运动神经元的关键部位）是MC 4-R表达的密集部位。因此，中央黑皮质素系统可能是一个重要的途径，感知和响应饥饿和饱足的信号，通过vaqa！和体液输入脑干黑皮质素系统，也许，在某些情况下，甚至直接作用于弓状POMC神经元的体液因素。其次，弓状和脑干POMC神经元将投射发送到参与自主流出的许多含MC 4-R的位点，如PVN、DMH、IML、PBL和DMV，并且将黑素皮质素化合物立体定位注射到PVN中可以深刻地影响进食行为。因此，由黑皮质素系统调节自主流出到肠道可能是该系统参与调节能量摄入的重要途径。在下一 在资助期内，我们将继续研究中枢黑皮质素系统的调节输入和效应器输出途径，重点关注该系统在感知和响应急性饥饿和饱足信号方面的作用。