Sex Differences in the Control of Feeding

描述(申请人提供)：下丘脑前阿片黑素皮质素原(POMC)神经元已被证明在能量平衡中发挥关键作用。这项拟议研究的长期目标是确定信号机制的差异(S)，雌激素(E_2)通过这种机制以性别特异性的方式调节阿片黑素皮质酮，并随后调节体内平衡功能。了解E2对POMC神经元的作用将有助于深入了解女性和男性在控制进食方面的根本差异，从而了解进食障碍，这在青春期后更常见的女性。这些差异的生物学基础尚不清楚，但可能涉及下丘脑POMC神经元及其对雌二醇和5-羟色胺(5HT)的反应。我们发现E_2可以通过解偶联MU-阿片受体和GABAB受体而迅速解除对雌性POMC神经元的抑制，并发现了一种膜相关的E_2受体(MER)，该受体与磷脂酶C-蛋白激酶C-蛋白激酶A途径Gq偶联，与已报道的5-羟色胺5TH_2A/C受体非常相似。此外，我们还合成了一种新的SERM，STX，它专门针对这个新的E2信号通路。E2(STX)的快速信号传递有许多下游靶点，包括解偶联POMC神经元K(GIRK)通道的G1，O偶联神经递质受体，从而增强神经元的活性。我们的假设是，在控制摄食和能量平衡方面的性别差异，部分是由于雌二醇对POMC神经元的去抑制作用比雄鼠更有效，并且MER和5HT2c细胞内信号通路以性别特异性的方式汇聚在POMC神经元中。在这项建议中，我们试图阐明雌二醇和5-羟色胺在两性中激活的细胞级联反应。我们将使用一系列独特的细胞、分子和化学工具来表征POMC神经元中的信号通路及其在男性和女性中的功能后果。其具体目的是：(1)检测STX对去性腺动物POMC神经元K通道上GABAB、f-阿片和5HTiA受体的解偶联作用。(2)勾画POMC神经元中5HT2a/c信号通路并确定其与MER信号通路的融合。(3)观察STX对去性腺雄性和雌性豚鼠摄食量和能量代谢的影响。(4)观察STX对野生型和内质网POMC神经元的影响。有缺陷的小鼠。这些研究的结果不仅有助于阐明控制摄食和能量平衡的下丘脑POMC神经元中雌激素和5-羟色胺信号通路的性别差异，而且可能有助于开发用于治疗饮食障碍的SERM。

DESCRIPTION (provided by applicant): Hypothalamic proopiomelanocortin (POMC) neurons have been shown to play a critical role in energy homeostasis. The long-range goal of the proposed research is to define the differences in signaling mechanism(s) by which estrogen (E2) modulates opiomelanocortin tone and subsequently homeostatic functions in a sex-specific manner. Understanding the actions of E2 on POMC neurons will provide insight into fundamental differences between females and males in the control of feeding, and as a consequence eating disorders, which are more common in females after puberty. The biological bases for these discrepancies are unknown, but likely involve hypothalamic POMC neurons and their response to E2 and serotonin (5HT) in a sex-specific manner. We have found that E2 can rapidly disinhibit female POMC neurons via uncoupling mu-opioid and GABAB receptors, and have identified a putative membrane-associated E2 receptor (mER) that is Gq-coupled to a phospholipase C-protein kinase C-protein kinase A pathway, which is very similar to what has been described for serotonin 5TH2A/C receptors. In addition, we have synthesized a new SERM, STX that specifically targets this novel E2 signaling pathway. Rapid signaling by E2 (STX) has a number of downstream targets including uncoupling G i,o coupled neurotransmitter receptors from K+ (GIRK) channels in POMC neurons, which enhances neuronal activity. Our hypothesis is that sex differences in the control of feeding and energy homeostasis are due, in part, to the greater efficacy of E2 in females versus males to dis-inhibit POMC neurons and that the mER and 5HT2c intracellular signaling pathways converge in POMC neurons in a sex specific manner. In this proposal, we seek to elucidate the cellular cascades activated by E2 and serotonin in both sexes. We will use a unique range of cellular, molecular and chemical tools to characterize the signaling pathways in POMC neurons and its functional consequences in both male and females. The specific aims are: (1) To test the efficacy of STX in gonadectomized animals to uncouple GABAB, f-opioid and 5HTiA receptors from K+ channels in POMC neurons. (2) To delineate the 5HT2A/c signaling pathway and determine its convergence with the mER signaling pathway in POMC neurons. (3) To measure the effects of STX on food intake and energy metabolism in gonadectomized male and female guinea pigs. (4) To measure the effects of STX on POMC neurons in wild type and ER? deficient mice. The results from these studies will not only help to elucidate sex differences in estrogen and serotonin signaling pathways in hypothalamic POMC neurons that control feeding and energy homeostasis, but potentially will allow the development of SERMs for treatment of eating disorders.