Characterization of Kiss1 neurons as mediators of the reproductive regulation of energy balance

摘要 生殖和新陈代谢受到密切的调节，以确保生物体和物种的生存。的 能量平衡的中枢控制依赖于中枢和外周信号的复杂相互作用， 最终调节食物摄入和能量消耗（EE）。在参与控制的中央信号中， 在能量平衡中，由前阿黑皮素（POMC）神经元产生的黑皮质素（a-MSH）起关键作用 α-MSH在黑皮质素受体4（MC 4 R）的水平上结合黑皮质素受体4（MC 4 R）。 然而，黑皮质素调节EE的作用位点仍然存在， 被低估了最近，由Kiss 1编码的生殖神经肽kisspeptin被鉴定出来， 例如，作为几种动物模型中的代谢因子，kisspeptin信号传导缺陷的小鼠发展成肥胖症。 Kisspeptin已被证明对生殖轴的激活是必不可少的，然而，它在生殖轴的激活中的作用是不可或缺的。 代谢需要进一步研究。我们的初步数据扩展了这些发现，并表明， Kiss 1神经元的黑皮质素信号参与EE的控制。 神经元a）表达MC 4 R，B）直接响应a-MSH的刺激，c）是POMC的直接靶点 神经元，其突触后调节Kiss 1神经元，和d）支配和激活Lepr神经元， 背内侧下丘脑（DMH）通过谷氨酸释放。此外，我们已经证明， 从Kiss 1神经元特异性去除MC 4 R诱导由于EE降低而导致的体重（BW）增加 而不改变总体食物摄入或活动，并且不引起性腺功能减退。因此，我们假设 Kiss 1神经元作为黑皮质素作用的介质，通过控制LeprDMH来调节EE 神经元，从而揭示了黑皮质素在控制能量平衡中的一种新的作用途径， 生殖和新陈代谢。我们建议：1）评估消融或慢性激活后EE的变化 Kiss 1神经元的数量; 2）评估Kiss 1神经元对EE的黑皮质素调节的总体贡献 通过在MC 4 RKO小鼠的Kiss 1神经元中重新插入MC 4 R; 3）绘制其背后的神经回路 通过识别神经元投射和Kiss 1神经元末梢的光遗传学激活发挥作用; 3） 评估kisspeptin共递质在EE控制中的贡献。Kiss 1神经元是结 生殖功能的调节中心，因此对性循环水平的变化敏感 类固醇.因此，成功完成这项提案可能是全面解决这一问题的第一个办法。 连接生殖状态和能量消耗调节的途径，可以解释经常发生的 观察到睾酮水平低的女性或男性绝经后体重增加。而且 Kiss 1神经元作为控制能量平衡的活跃参与者的特征将为开发 改善代谢紊乱治疗的新策略。

ABSTRACT Reproduction and metabolism are closely regulated to ensure the survival of the organism and the species. The central control of energy balance depends on the intricate interaction of central and peripheral signals that ultimately regulate food intake and energy expenditure (EE). Among the central signals involved in the control of energy balance, melanocortins (a-MSH) produced by proopiomelanocortin (POMC) neurons play a critical role inducing satiety and increasing EE. a-MSH binds the melanocortin receptor 4 (MC4R) at the level of the paraventricular nucleus to induce satiety, however, the site of action of melanocortins to regulate EE remains under-characterized. Recently, the reproductive neuropeptide kisspeptin, encoded by Kiss1, has been identified as a metabolic factor in several animal models, for example, kisspeptin signaling deficient mice develop obesity. Kisspeptin has been demonstrated to be essential for the activation of the reproductive axis, however, its role in metabolism requires further investigation. Our preliminary data expands on these findings and suggest that melanocortin signaling to Kiss1 neurons is involved in the control of EE. We have showed that Kiss1 neurons a) express MC4R, b) respond directly to the stimulation by a-MSH, c) are direct targets of POMC neurons, which post-synaptically regulate Kiss1 neurons, and d) innervate and activate Lepr neurons in the dorsomedial hypothalamus (DMH) through glutamate release. In addition, we have demonstrated that the specific removal of MC4R from Kiss1 neurons induces an increase in body weight (BW) due to a decrease in EE without changes in overall food intake or activity and without causing hypogonadism. Therefore, we hypothesize that Kiss1 neurons serve as mediators of the melanocortin action to regulate EE through the control of LeprDMH neurons, thus uncovering a novel pathway of action for melanocortins in the control of energy balance that links reproduction and metabolism. We propose to 1) evaluate the changes in EE after ablation or chronic activation of Kiss1 neurons; 2) assess the overall contribution of Kiss1 neurons to the melanocortin regulation of EE through the re-insertion of MC4R in Kiss1 neurons of MC4RKO mice; 3) map the neurocircuitry underlying this role through the identification of neuronal projections and optogenetic activation of Kiss1 neuron terminals; 3) assess the contribution of kisspeptin co-transmitters in the control of EE. Kiss1 neurons are the nodal regulatory center of reproductive function and are, therefore, sensitive to changes in the circulating levels of sex steroids. Thus, the successful completion of this proposal may offer the first approach to a comprehensive pathway linking reproductive status and the regulation of energy expenditure that could explain the frequently observed increase in BW after menopause in women or men with low testosterone. Moreover, the characterization of Kiss1 neurons as an active player in the control of energy balance will inform the development of new strategies to improve the treatment of metabolic disorders.