PROJECT 4 - Antagonistic Actions of Melanocortins and Leptin on Reproductive Comp

项目 4 - 黑皮质素和瘦素对生殖细胞的拮抗作用

• 批准号: 7684932
• 负责人: STREAMSON C CHUA
• 金额: $ 26.26万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7684932
• 关键词: Ablation; Address; Affect; Agonist; Alleles; Binding; Body Composition; Brain; Cell Nucleus; Cells; Competence; Data; Development; Diet; Eating; Endorphins; Feeding behaviors; Female; Fertility; Genes; Genetic; Genetically Engineered Mouse; Goals; Gonadotropins; Hypogonadism; Hypothalamic structure; Infertility; Knockout Mice; LEPR gene; Leptin; Medial; Mediating; Metabolism; Modeling; Mus; Neuroendocrine Cell; Neurons; Neuropeptides; Neurotransmitters; Obesity; Peptides; Preoptic Areas; Protein Isoforms; Receptor Signaling; Regulation; Reproductive Biology; Reproductive system; Role; Sexual Development; Signal Transduction; Site; Skeletal Muscle; Structure of nucleus infundibularis hypothalami; System; Testing; Transgenes; Transgenic Mice; Women' s Health; alpha-Melanocyte stimulating hormone; base; cell type; db/db mouse; energy balance; gamma-MSH; improved; leptin receptor; melanocortin receptor; melanotan-II; overexpression; reproductive; reproductive function; response; transmission process

A major regulator of body composition, energy balance and food intake is leptin, an adipocytokine [1]. Leptin circulates and has direct actions in the brain [2] and skeletal muscle [3, 4] by binding to the B isoform of leptin receptor (LEPR-B). Loss of leptin signaling also leads to hypothalamic hypogonadism and infertility. There are numerous hypothalamic nuclei that are responsive to leptin and each of these nuclei has numerous types of neurons, as defined by their neurotransmitter content [5, 6]. There are numerous lines of evidence which indicate leptin responsive neurons within the arcuate nucleus affect gonadotropin release. The orexigenic neuropeptides NPY [7, 8] and AGRP [9] have been shown to inhibit LH release. There are anatomical projections of arcuate nucleus neurons from NPY/AGRP neurons and from POMC (endorphin projections) [10] neurons to the medial preoptic area containing GnRH neurons [11]. Nevertheless, the functional impact of melanocortin modulation of GnRH neurons is not well characterized. We present preliminary data to suggest that melanocortin signaling is important to sexual development and reproductive competence within the context of leptin signaling deficiencies. We propose to study the role of melanocortinergic transmission in modulating GnRH neurons and reproductive function. The goals of this proposal are to examine the functional importance of melanocortinergic transmission in mediating the effects of leptin on GnRH neuronal function and reproductive competence. We have four specific aims that address the roles of leptin-regulated neuronal cell types in the regulation of the reproductive system. Aim 1. Determine the reproductive competence of mice with combined MC4R and LEPR deficiencies Aim 2, Determine the direct and indirect effects of melanocortins on GnRH neurons Aim 3. Determine the reproductive competence of increased melanocortinergic transmission in females with leptin receptor deficiency Aim 4. Determine the impact of restoring MC4R expression on GnRH neurons in females with combined MC4R and LEPR deficiencies

瘦素是调节身体组成、能量平衡和食物摄入的主要因素，它是一种脂肪细胞因子。瘦素循环