Melanocortin Signaling in Feeding Behavior

进食行为中的黑皮质素信号传导

• 批准号: 6879876
• 负责人: Roger D. Cone
• 金额: $ 28.97万
• 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/6879876
• 关键词: appetite regulatory center; bioenergetics; biological signal transduction; brain stem; cholecystokinin; dorsal motor nucleus; genetically modified animals; 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和死亡的主要原因。中枢黑皮质素系统是调节体重和成分的关键回路，人类黑皮质素 4 受体 (MC4-R) 单倍体不足是严重肥胖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透彻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，并最终确定治疗能量稳态紊乱的药物开发的潜在靶标。该领域的大部分研究都集中在瘦素对弓状阿黑皮质素原 (POMC) 神经元的调节，以及它们在介导长期脂肪抑制瘦素信号中的作用。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知方面的重要作用。使用 利用本实验室开发的弓状POMC和NPY神经元记录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，而且还受到PYY3-36、胰岛素、CCK和ghrelin等急性饥饿和饱腹因子的调节。同样，在此处提供的初步数据中，我们表明 MC4-R 信号传导也对胃排空有影响，从而确定了一种新的传出途径 通过该系统调节饱腹感。事实上，刚刚发表的关于 MC4-R 单倍体不足的人类的数据记录了这些人的严重食欲过盛，甚至可能暴饮暴食。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输到中枢神经系统。 POMC 也在脑干孤束核 (NTS) 核中一组特征不明确的神经元中表达，迷走神经背侧运动核是调节胃肠道功能的运动神经元的关键位点，也是 MC4-R 表达的密集位点。因此，中枢黑皮质素系统可能是通过 vaqa 感知和响应饥饿和饱腹感信号的重要途径！和脑干黑皮质素系统的体液输入，也许，在某些体液因素的情况下，甚至直接作用于弓形 POMC 神经元。其次，弓状和脑干 POMC 神经元将投射发送到许多涉及自主神经流出的含有 MC4-R 的位点，如 PVN、DMH、IML、PBL 和 DMV，并且将黑皮质素化合物立体定向注射到 PVN 可以深刻影响进食行为。因此，黑皮质素系统对肠道自主神经流出的调节可能是该系统参与能量摄入调节的重要途径。在这接下来 在资助期间，我们将继续表征中央黑皮质素系统的监管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腹感信号中的作用。