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: 10507935
• 负责人: Victor Manuel Navarro
• 金额: $ 55.84万
• 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/10507935
• 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; Glutamate Receptor; Glutamates; Goals; Gonadal Steroid Hormones; High Fat Diet; Homeostasis; Hypogonadism; Hypothalamic structure; Investigation; KISS1 gene; Knock-in; Knock-out; Label; Lead; Link; Maintenance; Maps; Mediating; Mediator of activation protein; Melanocortin 4 Receptor; Menopause; Metabolic; Metabolic Diseases; Metabolism; Mus; Neural Pathways; Neurokinin B; Neurons; Neuropeptides; Neurotransmitters; Nodal; Obesity; Organism; Pathway interactions; Patients; Peripheral; Phenotype; Physiological; Play; Polycystic Ovary Syndrome; 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 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.

摘要 繁殖和新陈代谢受到严格的调控，以确保有机体和物种的生存。这个 能量平衡的中央控制依赖于中枢和外周信号的复杂相互作用 最终控制食物摄入量和能量消耗(EE)。在参与控制的中央信号中 能量平衡，由前阿片黑素皮质素(POMC)神经元产生的黑素皮质素(a-MSH)起着至关重要的作用 诱导饱腹感和提高EE。A-MSH与黑素皮质素受体4(MC4R)在 室旁核诱导饱腹感，然而，黑素皮质素调节EE的作用部位仍然存在 不够有特色。最近，由Kiss1编码的生殖神经肽Kisspeptin被鉴定出来 例如，在几种动物模型中，Kispeptin作为代谢因素，信号缺陷的小鼠会出现肥胖。 Kispeptin已被证明对生殖轴的激活是必不可少的，然而，它在 新陈代谢需要进一步研究。我们的初步数据对这些发现进行了扩展，并表明 黑素皮质素对Kiss1神经元的信号参与了EE的控制。我们已经证明了Kiss1 神经元a)表达MC4R，b)对a-MSH的刺激有直接反应，c)是POMC的直接靶点 神经元，它在突触后调节Kiss1神经元，以及d)支配和激活Lepr神经元 背内侧下丘脑(DMH)通过释放谷氨酸。此外，我们还展示了 从Kiss1神经元特异性去除MC4R可导致体重增加，这是由于EE降低 不会改变整体食物摄入量或活动量，也不会引起性腺功能减退。因此，我们假设 Kiss1神经元作为黑素皮质素的介体，通过LeprDMH调节EE 神经元，从而揭示了黑素皮质素在控制能量平衡中的一条新的作用途径 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 Kiss1神经元；2)评估Kiss1神经元对EE的黑素皮质素调节的整体贡献 通过在MC4RKO小鼠的Kiss1神经元中重新插入MC4R；3)映射其背后的神经回路 通过识别神经元投射和Kiss1神经元终末的光发生激活来发挥作用；3) 评估Kispeptin共递质在EE控制中的作用。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很敏感 类固醇。因此，这项提案的成功完成可能会为全面的 生殖状态和能量消耗调节之间的联系可以解释频繁的 观察到，在睾酮水平较低的女性或男性绝经后体重增加。此外， Kiss1神经元作为控制能量平衡的积极参与者的特征将为这一发展提供信息 提出了改善代谢紊乱治疗的新策略。