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

• 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
• 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

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能力的关键调节剂，通过Kisspeptin受体（KISS1R）直接向GNRH神经元发出信号。此外，KISS1R在其他大脑区域和外围也表达，这表明Kisspeptin信号传导可能在繁殖之外具有其他作用。实际上，最近的工作表明，亲吻肽神经元可能调节与喂养和能量平衡有关的其他神经元种群。我的小说和令人兴奋的初步数据支持在代谢，肥胖和葡萄糖稳态中亲吻肽信号传导的作用。我发现成年Kiss1r敲除（KO）小鼠表现出一种性二态代谢表型，体重，身体成分，代谢率和葡萄糖稳态的鲜明异常，似乎独立于性类固醇的活性作用。我的新颖发现支持Kisspeptin信号通路在调节生殖轴（通过GNRH）和代谢/能量状态（通过未知途径）的作用。该NRSA项目将提供有关Kisspeptin-Kiss1R信号传导功能的新信息，并有可能对繁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育。该提议的目标是阐明Kiss1r KO小鼠的多效和性二态代谢表型的原因。 AIM 1确定代谢率缺陷是否先于KIS1R KO女性的成年早期肥胖。此目的使用代谢笼和激素测定法检查了几个参数，以确定KISS1R KO女性中代谢表型的发育开始。 AIM 2探讨了潜在受损的瘦素信号传导的作用以及下丘脑代谢基因的变化在控制Kiss1r KO雌性的肥胖表型中的作用。该目标有两个部分，其中第一个部分评估了在细胞，生理和行为水平的KISS1R KO小鼠中的功能性瘦素反应性。 AIM 2测试的第二部分如果在KISS1R KO女性中改变了参与食物摄入和代谢的下丘脑基因的表达水平。 AIM 3确定KISS1R KO表型中的戏剧性性二态性是否是由新生儿性类固醇引起的发育组织引起的，如果是这样，则会发生性类固醇受体途径。总体而言，该建议将为分子提供新颖的见解 以及具有干扰的Kisspeptin-Kiss1R信号传导的小鼠多效代谢表型的基础的细胞机制。该项目将更好地理解亲吻肽信号传导在繁殖和代谢之间的界面中的作用，并可能有助于更好地理解肥胖与不育之间的关系。