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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的繁殖和代谢受到密切调节，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央和外围信号的复杂相互作用最终调节食品摄入和能源消耗（EE）。在控制中涉及的中央信号中 proOpiomelanocortin（POMC）神经元产生的能量平衡，黑色皮质蛋白（A-MSH）起着关键作用诱导饱腹感和增加EE。 A-MSH结合黑色皮质素受体4（MC4R）的水平然而，旁牙性核诱导饱腹感，黑色素皮质素对EE的作用部位特征不足。最近，已经确定了由Kiss1编码的生殖神经肽亲肽素例如，作为几种动物模型的代谢因素，Kisspeptin信号传导缺乏小鼠会发展肥胖。然而，已经证明亲吻肽对于激活生殖轴是必不可少的，但是它的作用在代谢需要进一步研究。我们的初步数据扩展了这些发现，并建议对KISS1神经元的黑素皮质素信号传导与EE的控制有关。我们已经证明了Kiss1 神经元A）Express MC4R，B）直接对A-MSH刺激响应，C）是POMC的直接靶标神经元，突触后调节KISS1神经元，d）支配并激活LEPR神经元下丘脑（DMH）通过谷氨酸释放。此外，我们已经证明了由于EE的减少，从KISS1神经元中特异性去除MC4R会导致体重增加（BW）没有整体食物摄入或活动的变化，也不会引起性能不足。因此，我们假设 KISS1神经元充当黑色素质素作用的介体，以通过LEPRDMH的控制来调节EE 神经元，因此在能量平衡的控制中发现了黑色皮质素的新型作用途径繁殖和代谢。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黑色皮质素调控的总体贡献通过在MC4RKO小鼠的KISS1神经元中重新插入MC4R； 3）绘制此基础的神经通路通过鉴定神经元投影和KISS1神经元终端的光遗传激活的作用； 3）评估Kisspeptin共晶剂在控制EE中的贡献。 KISS1神经元是节点生殖功能的调节中心，因此对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提供第一种方法连接生殖状况和能源支出的调节的途径，可以解释经常在更年期后，男性或男性睾丸激素较低的男性观察到BW的增加。而且， KISS1神经元作为能量平衡控制的活跃参与者的表征将为发展提供信息改善代谢疾病治疗的新策略。