The ventromedial hypothalamus (VMH) plays chief roles regulating energy and glucose homeostasis and is sexually dimorphic. We discovered that expression of metabotropic glutamate receptor subtype 5 (mGluR5) in the VMH is regulated by caloric status in normal mice and reduced in brain-derived neurotrophic factor (BDNF) mutants, which are severely obese and have diminished glucose balance control. These findings led us to investigate whether mGluR5 might act downstream of BDNF to critically regulate VMH neuronal activity and metabolic function. We found that mGluR5 depletion in VMH SF1 neurons did not affect energy balance regulation. However, it significantly impaired insulin sensitivity, glycemic control, lipid metabolism, and sympathetic output in females but not in males. These sex-specific deficits are linked to reductions in intrinsic excitability and firing rate of SF1 neurons. Abnormal excitatory and inhibitory synapse assembly and elevated expression of the GABAergic synthetic enzyme GAD67 also cooperate to decrease and potentiate the synaptic excitatory and inhibitory tone onto mutant SF1 neurons, respectively. Notably, these alterations arise from disrupted functional interactions of mGluR5 with estrogen receptors that switch the normally positive effects of estrogen on SF1 neuronal activity and glucose balance control to paradoxical and detrimental. The collective data inform an essential central mechanism regulating metabolic function in females and underlying the protective effects of estrogen against metabolic disease.

下丘脑腹内侧区（VMH）在调节能量和葡萄糖稳态方面发挥着主要作用，并且具有性别二态性。我们发现，VMH 中代谢型谷氨酸受体亚型 5 (mGluR5) 的表达在正常小鼠中受热量状态调节，而在脑源性神经营养因子 (BDNF) 突变体中表达减少，这些突变体严重肥胖且葡萄糖平衡控制减弱。这些发现促使我们研究 mGluR5 是否可能在 BDNF 下游发挥作用，从而严格调节 VMH 神经元活动和代谢功能。我们发现 VMH SF1 神经元中 mGluR5 的消耗并不影响能量平衡调节。然而，它显着损害了女性的胰岛素敏感性、血糖控制、脂质代谢和交感神经输出，但男性则没有。这些性别特异性缺陷与 SF1 神经元内在兴奋性和放电率的降低有关。异常的兴奋性和抑制性突触组装以及 GABA 能合成酶 GAD67 的表达升高也分别协同降低和增强突变型 SF1 神经元的突触兴奋性和抑制性音调。值得注意的是，这些改变是由于 mGluR5 与雌激素受体的功能相互作用被破坏而引起的，这种相互作用将雌激素对 SF1 神经元活动和葡萄糖平衡控制的正常积极作用转变为矛盾和有害的作用。这些集体数据揭示了调节女性代谢功能的重要中心机制，以及雌激素对代谢疾病的保护作用。