Neurosteroid Regulation of Adiposity, Glucose Homeostasis and Energy Expenditure in Primates

神经类固醇对灵长类动物肥胖、血糖稳态和能量消耗的调节

基本信息

批准号：
10001506
负责人：
Jon E Levine
金额：
$ 59.6万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10001506
关键词：
Ablation Adult Androgens Aromatase Aromatase Inhibition Body Weight Brain CYP17A1 gene Callithrix Cell Nucleus Disease ESR1 gene Energy Metabolism Enzyme Inhibitor Drugs Enzymes Estradiol Estrogen Receptor alpha Estrogen Receptors Estrogens Excision Fatty acid glycerol esters Female Functional disorder Gene Expression Gene Silencing Genetic Gonadal Steroid Hormones Health Homeostasis Hypothalamic structure Impairment Insulin Resistance Lead Letrozole Ligands Light Macaca mulatta Mediating Metabolic Metabolic Control Metabolic Diseases Microdialysis Monkeys Neurons Neurosecretory Systems Obesity Oral Ovarian Ovariectomy Ovary Peripheral Pharmaceutical Preparations Pharmacology Physical activity Primates Procedures Production Regulation Risk Rodent Role Steroid Receptors Steroid biosynthesis Steroids Structure of nucleus infundibularis hypothalami System Testing Testosterone Therapeutic Tissues Viral Vector Woman adeno-associated viral vector blood glucose regulation design energy balance genetic manipulation glucose tolerance inhibitor/antagonist knock-down neuroregulation neurosteroids nonhuman primate novel novel therapeutic intervention relating to nervous system response small hairpin RNA therapeutic target

项目摘要

Estradiol (E2) in adult female rodents regulates body weight, adiposity, energy balance, physical activity and glucose homeostasis, as demonstrated by robust metabolic responses to ovariectomy, E2 replacement, and genetic manipulation of estrogen receptors. In female primates, however, removal of the ovaries does not reliably lead to increases in adiposity, insulin resistance or altered energy homeostasis. In recent studies, we have confirmed that neither ablation of peripheral E2 production nor E2 replacement alters adiposity, glucoregulation or energy homeostasis in marmoset monkeys, adding to previous evidence suggesting peripheral estrogens do not play important roles in female primate metabolic regulation. Our recent novel findings, however, demonstrate the critical importance of hypothalamic estrogen receptor alpha (ERα) in regulating metabolic function in a female nonhuman primate (NHP), as silencing of hypothalamic ERα gene expression induces obesity and insulin resistance in adult female rhesus monkeys. Taken together, these findings suggest that hypothalamic ERa may function in NHPs, as it does in rodents, to regulate adiposity, glucoregulation and energy homeostasis, yet peripherally produced E2 has diminished importance in engaging these actions. Recent studies have suggested that neurosteroidogenesis, specifically hypothalamic aromatization by CYP19A1 of androgen precursors to E2, may regulate neural control of metabolic function in NHPs. We have therefore formulated a new hypothesis that E2 synthesized in the brain, specifically in neurons of the ventromedial nucleus (VMN) and arcuate nucleus (ARC) of the hypothalamus, activates ERα to regulate adiposity, glucoregulation and energy homeostasis in female NHPs. To test this hypothesis, we will use both pharmacological and viral vector- mediated shRNA approaches to determine if adiposity, glucoregulation and energy metabolism are altered by inhibition of the CYP19A1 aromatase enzyme, or by permanent silencing of the CYP19A1 gene in the hypothalamus of female rhesus macaques. We will also analyze the synthesis of E2 in the VMN and ARC by a microdialysis approach, and determine whether VMN and ARC E2 originates from hypothalamically synthesized androgens. These studies may fundamentally change our understanding of metabolic control of adiposity, glucoregulation and energy homeostasis by sex steroids in female NHPs, and prompt exploration of new therapeutic strategies to diminish metabolic disease in women.

成年啮齿动物体重，肥胖，能量平衡，体育锻炼和葡萄糖稳态中的雌二醇（E2），通过对卵巢的鲁棒代谢反应，E2替代和雌激素受体的遗传操纵。胰岛素抵抗或能量稳态改变。在女性非人类灵长类动物（NHP）YpothalamicERα基因中的功能可阐明肥胖症，而雌性恒河猴可能在NHP中起作用，就像在啮齿动物中一样提出神经固醇生成N的前体对E2的前体可以调节NHP中代谢功能的神经控制，因此我们提出了一种新的假设，即E2在大脑中合成，特别是在内侧核（VMN）的神经元中, activates ERα to regulate adiposity, glucoregulation and energy homeostasis in female NHPs. To test this hypothesis, we will use both pharmacological and viral vector- mediated shRNA approaches to determine IF Adiposity, GlucoreGy Metabolism Are Altered of the Cyp19a1 Aromatase ENZYME Ene in The Hypothharamus女性猕猴。女性NHPS tegies会减少女性代谢疾病。