Astrocyte insulin resistance-induced neuroendocrine defects in pubertal delay and hypogonadotropic hypogonadism

星形胶质细胞胰岛素抵抗诱导青春期延迟和低促性腺激素性性腺功能减退症的神经内分泌缺陷

• 批准号: 10612727
• 负责人: Jennifer Wootton Hill
• 金额: $ 55.17万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612727
• 关键词: Ablation; Adult; Age; Anabolism; Antral; Astrocytes; Biological; Blood - brain barrier anatomy; Body fat; Brain; Breeding; Calories; Cell Line; Cells; Communication; Complement; Coupling; Data; Defect; Delayed Puberty; Diabetes Mellitus; Dinoprostone; Drops; Eating; Enzymes; Female; Fertility; Food deprivation (experimental); Genes; Genetic; Genetic Transcription; Glial Fibrillary Acidic Protein; Goals; Gonadotropin Hormone Releasing Hormone; Homeostasis; Hormones; Idiopathic Hypogonadotropic Hypogonadism; Impairment; Improve Access; Individual; Infertility; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Insulin-Like Growth Factor I; Intermediate Filament Proteins; KISS1 gene; Klinefelter' s Syndrome; Leptin; Measurement; Measures; Menarche; Metabolic; Metabolic Diseases; Metabolic hormone; Molecular; Mus; Neuroglia; Neurons; Neurosecretory Systems; Nutrient; Obesity; Pathway interactions; Patients; Phosphorylation; Play; Population; Preoptic Areas; Presynaptic Terminals; Production; Prostaglandin-Endoperoxide Synthase; Puberty; Radial; Reproduction; Research; Role; Signal Pathway; Signal Transduction; Sperm Count Procedure; Strenuous Exercise; Structure of nucleus infundibularis hypothalami; Synapses; System; Testing; Therapeutic; Time; Viral; Western Blotting; Woman; Work; cyclooxygenase 2; diabetic; girls; glucose uptake; in vivo; insulin signaling; male; men; nerve stem cell; nestin protein; neurochemistry; novel therapeutics; obesity in children; peripubertal period; postsynaptic; presynaptic; promoter; pubertal timing; regenerative; reproductive; reproductive axis; reproductive function; reproductive hormone; response; sensor; sex; spatiotemporal; success; transcription factor

Astrocytes are known to provide support to gonadotropin releasing hormone (GnRH) neurons that control the reproductive axis, for example by releasing prostaglandin E2 (PGE2) required for fertility. Astrocytes may also play a critical role in the brain as metabolic sensors. In response to insulin, astrocytes increase glucose uptake across the blood brain barrier and release metabolites and gliotransmitters to support neuronal function. We have recently demonstrated a unique biological role for astrocytes in coupling fertility to energy availability. We found that the absence of insulin signaling in astrocytes delays puberty, causes hypogonadotropic hypogonadism, and dramatically reduces fertility. This finding is particularly exciting since numerous studies have shown neuronal insulin sensing is unnecessary for reproduction. We have also found that loss of astrocyte insulin sensing reduces PGE2 synthase levels, leading us to hypothesize that astrocyte insulin sensing facilitates GnRH release by promoting astrocyte PGE2 release. New preliminary data suggest that insulin signaling via FOXO pathways alter the transcription of enzymes in the PGE2 biosynthesis pathway, such as COX-2. We will test our hypothesis by pursuing three specific aims. Aim 1) Define the relevant temporal & spatial parameters of astrocyte insulin signaling. Using the tet-on genetic targeting system, we will test whether astrocytes must sense insulin during adulthood or prior to puberty in order to permit normal reproductive function. Astrocyte-specific viral cre administration will also determine the importance of astrocyte insulin sensing in the arcuate nucleus and the rostral preoptic area. Aim 2) Determine the impact of insulin signaling on astrocyte PGE2 gliotransmitter production proximal to reproductive circuits. Measurement of regional PGE2 production will be complemented by AAV targeted disruption of Cox-2 production by astrocytes to determine its importance for fertility. Finally, we will determine whether Kiss1 neurons sense PGE2, leading to altered GnRH release. Aim 3) Determine the molecular role of the insulin/ FOXO pathway in astrocyte PGE2 synthesis. An astrocyte cell line will be used to systematically investigate the major aspects of insulin/FOXO/COX signaling, including phosphorylation, localization, promoter occupancy, and quantitative transcriptional activity measurements. Finally, we will ablate insulin signaling pathways in astrocytes to determine their effect on fertility and PGE2 production. Collectively, these studies will identify how insulin signaling in astrocytes sustains reproductive circuit function. This work will elucidate what may be the dominant mechanism in the mammalian brain whereby insulin permits normal fertility and pubertal maturation. Our results will advance our long-term goal of finding treatment targets for impaired fertility in patients recovering from energy deficits, obese and diabetic populations, and others with idiopathic hypogonadotropic hypogonadism.

已知星形胶质细胞为控制促性腺激素释放激素（GnRH）的神经元提供支持