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

雌二醇（E2）在成年雌性啮齿动物中调节体重、肥胖、能量平衡、身体活动和葡萄糖稳态，这已被卵巢切除术、E2替代和雌激素受体基因操纵的强大代谢反应所证明。然而，在雌性灵长类动物中，切除卵巢并不一定会导致肥胖、胰岛素抵抗或能量稳态改变的增加。在最近的研究中，我们已经证实，切除外周E2的产生和E2的替代都不会改变狨猴的肥胖、血糖调节或能量稳态，这进一步证明了外周雌激素在雌性灵长类动物的代谢调节中并不起重要作用。然而，我们最近的新发现表明，下丘脑雌激素受体α (ERα)在调节雌性非人灵长类动物（NHP）的代谢功能中至关重要，因为下丘脑ERα基因表达沉默可诱导成年雌性恒河猴肥胖和胰岛素抵抗。综上所述，这些发现表明下丘脑ERa可能在NHPs中发挥作用，就像在啮齿动物中一样，调节肥胖、血糖调节和能量稳态，但外周产生的E2在参与这些作用方面的重要性有所降低。最近的研究表明，神经甾体生成，特别是雄激素前体E2的CYP19A1下丘脑芳构化，可能调节NHPs代谢功能的神经控制。因此，我们提出了一个新的假设，即E2在大脑中合成，特别是在下丘脑腹内侧核（VMN）和弓形核（ARC）的神经元中，激活ERα来调节女性NHPs的肥胖、血糖调节和能量稳态。为了验证这一假设，我们将使用药理学和病毒载体介导的shRNA方法来确定雌性恒河猴下丘脑中CYP19A1芳香化酶的抑制或CYP19A1基因的永久沉默是否会改变肥胖、血糖调节和能量代谢。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是否来源于下丘脑合成的雄激素。这些研究可能会从根本上改变我们对女性NHPs中性类固醇代谢控制肥胖、血糖调节和能量稳态的认识，并促进探索新的治疗策略以减少女性代谢疾病。

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.