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：
10649709
负责人：
Jon E Levine
金额：
$ 59.8万
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/10649709
关键词：
Ablation Adult Androgens Aromatase Aromatase Inhibition Body Weight Brain CYP17A1 gene Callithrix Cell Nucleus Dialysis procedure 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 Macaca mulatta Mediating Metabolic Metabolic Control Metabolic Diseases Microdialysis Monkeys Neurons Neurosecretory Systems Obesity Oral Ovarian Ovariectomy Ovary Peripheral Pharmaceutical Preparations Physical activity Primates Production Regulation Risk Reduction 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 knock-down neural neuroregulation neurosteroids nonhuman primate novel novel therapeutic intervention pharmacologic 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.

成年雌性啮齿动物中的雌二醇（E2）调节体重，肥胖，能量平衡，体育锻炼和葡萄糖稳态，如对卵巢切除术，E2替代和雌激素受体的基因操纵的强大代谢反应所证明的那样。然而，在女性灵长类动物中，去除卵巢并不能可靠地导致肥胖，胰岛素抵抗或能量稳态改变。在最近的研究中，我们已经证实，外围E2产生的消融和E2的替代品都不会改变果仁猴猴子中的肥胖，葡萄糖调节或能量稳态，这增加了以前的证据，表明外周种雌激素在女性灵长类女性灵长类女性灵长类动物中没有重要作用。然而，我们最近的新发现表明，下丘脑雌激素受体α（ERα）在女性非人类灵长类动物（NHP）中的调节代谢功能中的重要性，因为下丘脑ERα基因表达的沉默会诱导成年雌性rhesus monkeys肥胖和胰岛素抵抗。综上所述，这些发现表明下丘脑时代可能在NHP中起作用，就像在啮齿动物中一样，用于调节肥胖，葡萄糖调节和能量稳态，但外周产生的E2在参与这些动作方面的重要性降低了。最近的研究表明，雄激素前体对E2的CYP19A1特别是下丘脑芳香化的神经生成可能调节NHP中代谢功能的神经元。因此，我们提出了一个新的假设，即E2在大脑中合成，特别是在腹侧核（VMN）的神经元和下丘脑的弧形核（ARC）中，激活ERα以调节女性NHP中的ERα以调节肥胖，糖调节和能量稳态。为了检验这一假设，我们将使用药理学和病毒载体介导的ShRNA方法来确定通过抑制CYP19A1芳香酶酶的肥胖，葡萄糖调节和能量代谢是否会改变，或通过永久性的CYP19A1基因对MACAESSMACASUS的假设中的CYP19A1基因进行沉默。我们还将通过微透析方法分析VMN和ARC中E2的合成，并确定VMN和ARC E2是否起源于下丘脑合成的雄激素。这些研究可能从根本上改变了我们对女性NHP中性别立体素的代谢控制，葡萄糖调节和能量稳态的理解，并迅速探索了新的治疗策略，以减少女性代谢疾病。