Melanocortin Signaling in Feeding Behavior

肥胖是糖尿病、心血管疾病和癌症的危险因素，是发病率和死亡率的主要原因。中枢黑素皮质素系统是调节体重和成分的关键回路，人类黑素皮质素-4受体(MC4-R)单倍体缺乏是导致严重肥胖的最常见单基因原因，占病例的5%。因此，对中枢黑素皮质素系统的深入了解将增加我们对肥胖的理解，提高对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点。该领域的大部分研究都集中在瘦素对弓状前阿片黑素皮质素(POMC)神经元的调节，以及它们在介导长期脂肪瘦素信号中的作用。从这笔赠款的第一个资助期开始的研究也证明了黑素皮质素系统在饱腹感和营养摄入量感知方面的重要作用。使用 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，而且还受到急性饥饿和饱足因素的调节，如PYY3-36、胰岛素、CCK和Ghrelin。同样，在这里提供的初步数据中，我们表明MC4-R信号也对胃排空有影响，确定了一种新的传出途径 这一系统对饱腹感的调节。事实上，刚刚在MC4-R单倍体缺陷人类上发表的数据表明，这些人存在严重的吞噬过度，甚至可能是暴饮暴食。这些发现提出了两个耐人寻味的假设。首先，大多数饥饿和饱腹感的信号通过迷走神经传入和体液传入脑干传递到中枢神经系统。POMC在脑干孤束核(NTS)的神经元中也有表达，迷走神经背侧运动核是运动神经元调节胃肠道功能的关键部位，也是MC4-R表达的密集部位。因此，中枢黑素皮质素系统可能是感觉和反应饥饿和饱足信号的重要途径！和体液输入到脑干黑素皮质素系统，也许在一些体液因素的情况下，甚至直接作用于弓状POMC神经元。其次，弓状核和脑干POMC神经元向PVN、DMH、IML、PBL和DMV等涉及自主神经流出的许多含有MC4-R的部位发送投射，向PVN立体定向注射黑素皮质激素Jn化合物可以深刻地影响摄食行为。因此，黑素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。在接下来的这个 在供资期间，我们将继续确定中央黑素皮质素系统和效应器输出途径的调节输入的特征，重点是该系统在感知和应对严重饥饿和饱腹感信号方面的作用。

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.