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

Kiss1 神经元作为能量平衡生殖调节介质的表征

• 批准号: 10682484
• 负责人: Victor Manuel Navarro
• 金额: $ 56.62万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-12 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682484
• 关键词: Ablation; Animal Model; Binding; Body Weight; Brown Fat; CASP3 gene; Carbon Dioxide; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Consumption; Cues; Data; Dependovirus; Development; Eating; Energy Metabolism; Ensure; Evaluation; Excision; Female; Fertility; Food Energy; Genetic; Glutamates; Goals; Gonadal Steroid Hormones; High Fat Diet; Homeostasis; Hypogonadism; Hypothalamic structure; Investigation; KISS1 gene; Knock-in; Knockout Mice; Label; Link; Maintenance; Maps; Mediating; Mediator; Melanocortin 4 Receptor; Menopause; Metabolic; Metabolic Diseases; Metabolism; Mus; Neural Pathways; Neuroanatomy; Neurokinin B; Neurons; Neuropeptides; Neurotransmitters; Nodal; Obesity; Organism; Pathway interactions; Patients; Peripheral; Phenotype; Physiological; Play; Polycystic Ovary Syndrome; Postmenopause; Pregnancy; Pro-Opiomelanocortin; Production; Regulation; Regulatory Pathway; Reproduction; Role; Satiation; Signal Transduction; Site; Testing; Testosterone; Thermogenesis; Weight Gain; Woman; alpha-Melanocyte stimulating hormone; energy balance; improved; insight; knock-down; leptin receptor; male; men; metabolic phenotype; neural circuit; neuromechanism; novel; optogenetics; paraventricular nucleus; postsynaptic; postsynaptic neurons; preservation; receptor; reproductive; reproductive axis; reproductive function; restoration; transmission process

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.

抽象的 繁殖和新陈代谢受到严格调节，以确保生物体和物种的生存。这 能量平衡的中央控制取决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）。参与控制的中央信号之一 能量平衡中，阿片黑皮质素原 (POMC) 神经元产生的黑皮质素 (a-MSH) 发挥着关键作用 诱导饱腹感并增加能量效率。 a-MSH 在以下水平结合黑皮质素受体 4 (MC4R) 室旁核诱导饱腹感，然而，黑皮质素调节 EE 的作用位点仍然存在 特征不足。最近，由 Kiss1 编码的生殖神经肽 Kisspeptin 被鉴定出来。 作为多种动物模型中的代谢因素，例如，Kisspeptin 信号传导缺陷的小鼠会出现肥胖。 Kisspeptin 已被证明对于生殖轴的激活至关重要，然而，它的作用 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 黑皮质素向 Kiss1 神经元发出的信号参与 EE 的控制。我们已经证明 Kiss1 神经元 a) 表达 MC4R，b) 直接响应 a-MSH 的刺激，c) 是 POMC 的直接目标 神经元，突触后调节 Kiss1 神经元，d) 神经支配并激活 下丘脑背内侧 (DMH) 通过谷氨酸释放。此外，我们还证明了 从 Kiss1 神经元中特异性去除 MC4R 会因 EE 减少而导致体重 (BW) 增加 不会改变总体食物摄入量或活动，也不会引起性腺功能减退症。因此，我们假设 Kiss1 神经元充当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，该途径链接 繁殖和新陈代谢。我们建议 1) 评估消融或慢性激活后 EE 的变化 Kiss1 神经元； 2) 评估 Kiss1 神经元对 EE 黑皮质素调节的总体贡献 通过将 MC4R 重新插入 MC4RKO 小鼠的 Kiss1 神经元中； 3）绘制其背后的神经回路图 通过识别神经元投射和 Kiss1 神经元末梢的光遗传学激活来发挥作用； 3） 评估 Kisspeptin 协同递质在 EE 控制中的贡献。 Kiss1 神经元是节点 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，该提案的成功完成可能会为全面的解决方案提供第一种方法。 将生殖状态与能量消耗调节联系起来的途径可以解释频繁的 观察到睾酮水平较低的女性或男性绝经后体重增加。此外， Kiss1 神经元作为能量平衡控制中的积极参与者的特征将为发育提供信息 改善代谢紊乱治疗的新策略。