The Effects of Deficient Kisspeptin Signaling on Body Weight and Metabolism

Kisspeptin 信号传导缺陷对体重和代谢的影响

基本信息

批准号：
8647440
负责人：
Kristen Petersen Tolson
金额：
$ 5.7万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-15 至 2016-05-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8647440
关键词：
ART protein Adipose tissue Adult Androgen Receptor Animals Area Behavior Behavioral Biological Assay Biological Neural Networks Body Composition Body Weight Body fat Brain Brain region Data Defect Development Eating Energy Metabolism Estrogen Receptors Fatty acid glycerol esters Female Fertility Genes Goals Gonadal Steroid Hormones Hormones Human Hypothalamic structure Impairment Infertility Knock-out Knockout Mice Leptin Leptin resistance Mammals Metabolic Metabolic Diseases Metabolism Modeling Molecular Motor Activity Mus National Research Service Awards Neonatal Neurons Neuropeptides Newborn Infant Obesity Pathway interactions Phenotype Physiological Physiology Population Pro-Opiomelanocortin Puberty Receptor Signaling Regulation Reproduction Research Proposals Resistance Role Secondary to Serum Sex Characteristics Signal Pathway Signal Transduction Steroid Receptors Steroids Testing Time Translating Work blood glucose regulation emerging adult energy balance feeding innovation insight kisspeptin male neuropeptide Y novel public health relevance receptor reproductive reproductive axis response sexual dimorphism trait

项目摘要

DESCRIPTION (provided by applicant): Kisspeptin (encoded by Kiss1) is a key regulator of puberty and adult fertility, signaling directly to GnRH neurons through the kisspeptin receptor (Kiss1r). Additionally, Kiss1r is also expressed in other brain regions and in the periphery, suggesting that kisspeptin signaling may have additional roles outside of reproduction. Indeed, recent work indicates that kisspeptin neurons may regulate other neuronal populations implicated in feeding and energy balance. My novel and exciting preliminary data supports a role for kisspeptin signaling in metabolism, obesity, and glucose homeostasis. I found that adult Kiss1r knockout (KO) mice display a sexually dimorphic metabolic phenotype, with stark abnormalities in body weight, body composition, metabolic rate, and glucose homeostasis, which appears to be independent of activational actions of sex steroids. My novel findings support a role for kisspeptin signaling pathways in regulation of both the reproductive axis (via GnRH) and metabolic/energetic status (via unknown pathways). This NRSA project will provide new information on kisspeptin-Kiss1r signaling functions and has the potential to provide new insight into the interplay between reproduction and energy balance, and may translate to human metabolic diseases and infertility. This proposal's goal is to elucidate the causes of the pleiotropic and sexually dimorphic metabolic phenotype of the Kiss1r KO mice. Aim 1 determines if defects in metabolic rate precede the early adulthood obesity seen in Kiss1r KO females. This Aim examines several parameters using metabolic cages and hormone assays to determine the developmental onset of metabolic phenotypes in Kiss1r KO females. Aim 2 explores the role of potentially impaired leptin signaling and changes in hypothalamic metabolic genes in governing the obese phenotype of Kiss1r KO females. This Aim has two parts, the first of which assesses functional leptin responsiveness in Kiss1r KO mice at the cellular, and physiological, and behavioral levels. The second part of Aim 2 tests if expression levels of hypothalamic genes involved in food intake and metabolism are altered in Kiss1r KO females. Aim 3 determines if the dramatic sexual dimorphism in the Kiss1r KO phenotype is caused by developmental organization induced by neonatal sex steroids, and if so, via which sex steroid receptor pathways this occurs. Overall, this proposal will provide novel insight into the molecular and cellular mechanisms underlying the pleiotropic metabolic phenotype of mice with disrupted kisspeptin-Kiss1r signaling. This project will provide better understanding of the role of kisspeptin signaling at the interface between reproduction and metabolism, and may help to better understand the relationship between obesity and infertility.

描述（由申请人提供）：Kisspeptin（由 Kiss1 编码）是青春期和成人生育力的关键调节因子，通过 Kisspeptin 受体 (Kiss1r) 直接向 GnRH 神经元发出信号。此外，Kiss1r 也在其他大脑区域和外周表达，这表明 Kisspeptin 信号传导可能在生殖之外发挥其他作用。事实上，最近的研究表明 Kisspeptin 神经元可能调节与进食和能量平衡有关的其他神经元群。我的新颖且令人兴奋的初步数据支持 Kisspeptin 信号在新陈代谢、肥胖和葡萄糖稳态中的作用。我发现成年 Kiss1r 敲除 (KO) 小鼠表现出性别二态性代谢表型，体重、身体成分、代谢率和葡萄糖稳态明显异常，这似乎与性类固醇的激活作用无关。我的新发现支持 Kisspeptin 信号通路在生殖轴（通过 GnRH）和代谢/能量状态（通过未知通路）调节中的作用。该 NRSA 项目将提供有关 Kisspeptin-Kiss1r 信号传导功能的新信息，并有可能为生殖和能量平衡之间的相互作用提供新的见解，并可能转化为人类代谢疾病和不孕症。该提案的目标是阐明 Kiss1r KO 小鼠多效性和性二态性代谢表型的原因。目标 1 确定 Kiss1r KO 雌性中代谢率缺陷是否先于成年早期肥胖。该目标使用代谢笼和激素测定检查多个参数，以确定 Kiss1r KO 雌性代谢表型的发育起始。目标 2 探讨潜在受损的瘦素信号传导和下丘脑代谢基因的变化在控制 Kiss1r KO 雌性肥胖表型中的作用。该目标分为两个部分，第一部分评估 Kiss1r KO 小鼠在细胞、生理和行为水平上的功能性瘦素反应性。 Aim 2 的第二部分测试 Kiss1r KO 雌性中涉及食物摄入和代谢的下丘脑基因的表达水平是否发生改变。目标 3 确定 Kiss1r KO 表型中显着的性别二态性是否是由新生儿性类固醇诱导的发育组织引起的，如果是，则确定这种现象是通过哪种性类固醇受体途径发生的。总体而言，该提案将为分子生物学提供新的见解以及 Kisspeptin-Kiss1r 信号通路破坏的小鼠多效性代谢表型背后的细胞机制。该项目将更好地理解 Kisspeptin 信号在生殖和代谢之间的作用，并可能有助于更好地理解肥胖和不孕之间的关系。