Sex Differences in the Control of Feeding

喂养控制的性别差异

• 批准号: 7018455
• 负责人: Martin Jeffrey Kelly
• 金额: $ 32.44万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7018455
• 关键词: GABA receptor; behavioral /social science research tag; bioenergetics; eating; eating disorders; estrogen receptors; estrogens; gender difference; guinea pigs; hormone regulation /control mechanism; laboratory mouse; male castration; opioid receptor; ovariectomy; potassium channel; proopiomelanocortin; selective estrogen receptor modulators; serotonin receptor

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.

描述（由申请人提供）：下丘脑前阿黑皮素（POMC）神经元已被证明在能量稳态中起关键作用。拟议研究的长期目标是确定雌激素（E2）调节阿黑皮素张力和随后以性别特异性方式调节稳态功能的信号传导机制的差异。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，以及由此导致的进食障碍，这在青春期后的女性中更为常见。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E2和5-羟色胺（5-HT）的反应。我们已经发现，E2可以通过解偶联μ-阿片和GABAB受体快速解除对雌性POMC神经元的抑制，并且已经鉴定了一种推定的膜相关E2受体（mER），其与磷脂酶C-蛋白激酶C-蛋白激酶A途径Gq偶联，这与5-羟色胺5TH 2A/C受体的描述非常相似。此外，我们还合成了一种新的SERM，STX，专门针对这种新的E2信号通路。通过E2（STX）的快速信号传导具有许多下游靶点，包括从POMC神经元中的K+（GIRK）通道解偶联G1，0偶联的神经递质受体，其增强神经元活性。我们的假设是，性别差异的控制喂养和能量的稳态是由于，在一定程度上，更大的功效，E2在女性与男性解除抑制POMC神经元和mER和5 HT 2c细胞内信号通路会聚在POMC神经元中的性别特异性的方式。在这个建议中，我们试图阐明E2和血清素激活的细胞级联在两种性别。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。具体目标是：（1）在去性腺动物中检测STX对POMC神经元K+通道上GABAB、f-阿片和5 HT 1A受体的解偶联作用。(2)目的：探讨POMC神经元5 HT 2A/c信号通路及其与mER信号通路的衔接。(3)研究STX对去势雄性和雌性豚鼠摄食量和能量代谢的影响。(4)为了测量STX对野生型和ER的POMC神经元的影响？缺陷小鼠这些研究的结果不仅有助于阐明控制进食和能量稳态的下丘脑POMC神经元中雌激素和5-羟色胺信号通路的性别差异，而且可能允许开发用于治疗进食障碍的SERM。