Sex Differences in the Control of Feeding

描述（由申请人提供）：下丘脑原阿黑皮质素（POMC）神经元已被证明在能量稳态中发挥关键作用。本研究的长期目标是确定雌激素 (E2) 调节阿黑皮质素张力以及随后以性别特异性方式调节体内平衡功能的信号机制的差异。了解 E2 对 POMC 神经元的作用将有助于了解女性和男性在进食控制方面的根本差异，以及由此产生的饮食失调，这种情况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 神经元及其以性别特异性方式对 E2 和血清素 (5HT) 的反应。我们发现 E2 可以通过解偶联 mu-阿片类药物和 GABAB 受体来快速解除对雌性 POMC 神经元的抑制，并鉴定出一种推定的膜相关 E2 受体 (mER)，该受体与磷脂酶 C-蛋白激酶 C-蛋白激酶 A 通路 Gq 偶联，这与血清素 5TH2A/C 受体的描述非常相似。此外，我们还合成了一种新的 SERM，STX，专门针对这种新型 E2 信号通路。 E2 (STX) 的快速信号传导具有许多下游靶标，包括从 POMC 神经元中的 K (GIRK) 通道解偶联 G i,o 偶联神经递质受体，从而增强神经元活性。我们的假设是，摄食和能量稳态控制方面的性别差异部分是由于E2在雌性中比雄性中更有效地解除对POMC神经元的抑制，并且mER和5HT2c细胞内信号通路以性别特异性方式在POMC神经元中汇聚。在本提案中，我们试图阐明 E2 和血清素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）测试STX在去性腺切除动物中将GABAB、f-阿片类药物和5HTiA受体与POMC神经元的K通道解偶联的功效。 (2)描绘POMC神经元中5HT2A/c信号通路并确定其与mER信号通路的收敛性。 (3)测定STX对去性腺切除的雄性和雌性豚鼠食物摄入和能量代谢的影响。 (4) 测量STX对野生型和ER？POMC神经元的影响？缺乏的老鼠。这些研究的结果不仅有助于阐明控制摄食和能量稳态的下丘脑 POMC 神经元中雌激素和血清素信号通路的性别差异，而且可能有助于开发用于治疗饮食失调的 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.