Sex-specific effects of mGluR5 in the VMH influencing glucose homeostasis

项目摘要 脑源性神经营养因子（BDNF）是兴奋性突触可塑性的主要调节因子， 这种神经营养素功能的减弱与人类的肥胖和代谢功能障碍有关， 啮齿动物我们发现，具有整体中枢BDNF缺失（BDNF 2L/2LCk-cre）的小鼠表现出肥胖、胰岛素分泌和胰岛素抵抗。 抵抗、高血糖和血脂异常。这些发现具有重要的临床意义， BdnfVal 66 Met变体干扰BDNF信号传导，在人类中非常普遍。先前 研究结果表明，腹内侧下丘脑（VMH），一个关键区域的能量和葡萄糖， 平衡控制，是BDNF作用的重要部位。BDNF的作用机制是 定义不明确，特别是那些独立于进食控制的动物。该提案将调查 代谢型谷氨酸受体5（mGluR 5）介导BDNF对VMH神经元作用的新机制 活动和血糖控制。这源于我们发现mGluR 5的表达在糖尿病患者中是显著的。 BDNF 2L/2LCk-cre突变体的VMH降低。mGluR 5在VMH中高度表达，并存在于神经元中 （包括SF 1+）和星形胶质细胞在这个区域，并发挥重要作用，兴奋性突触可塑性， 成人大脑值得注意的是，我们发现在VMH SF 1+神经元中选择性缺失mGluR 5显著地降低了VMH SF 1+神经元中mGluR 5的表达。 突变体（mGluR 5 f/f：SF 1-cre）中血糖控制和脂质代谢受损，但不影响体重 但在雄性小鼠中没有。因此，我们假设mGluR 5作用于BDNF下游，介导 葡萄糖和脂质稳态的体重无关和性别特异性的方式，通过提高兴奋性 SF 1+神经元的张力。目的1将检验mGluR 5在SF-1+神经元中的性别特异性作用的假设， 涉及与雌激素受体（ER）的功能性相互作用。目标2包括解剖学， 电生理和分子研究确定mGluR 5调节活性的性别特异性作用， SF 1+神经元，目标3将定义由ER-mGluR 5控制的SF 1+神经元的分子机制 相互作用，以控制神经元活动和葡萄糖和脂质稳态，目标4将测试是否 BDNF对代谢功能的影响是由雌性中mGluR 5-ER功能相互作用介导的。在 总的来说，这些研究将告知新的机制介导葡萄糖稳态和新的 解决糖尿病及其相关并发症的途径。特别是，它将通知上级 绝经后妇女报告的胰岛素抵抗和代谢紊乱的风险。

Project Summary Brain-derived neurotrophic factor (BDNF) is a chief regulator of excitatory synaptic plasticity, and diminished function of this neurotrophin is associated with obesity and metabolic dysfunction in humans and rodents. We showed that mice with global central BDNF depletion (BDNF2L/2LCk-cre) exhibit obesity, insulin resistance, hyperglycemia and dyslipidaemia. These findings have significant clinical implications as the BdnfVal66Met variant, which interferes with BDNF signaling, is highly prevalent in humans. Previous findings indicate that the ventromedial hypothalamus (VMH), a critical region for energy and glucose balance control, is an important site of BDNF action. The mechanisms underlying the effects of BDNF are poorly defined, especially those acting independently from feeding control. This proposal will investigate the novel role of metabotropic glutamate receptor 5 (mGluR5) mediating effects of BDNF on VMH neuronal activity and glycemic control. It emanates from our discovery that mGluR5 expression is significantly reduced in VMH of BDNF2L/2LCk-cre mutants. mGluR5 is highly expressed in the VMH and present in neurons (including SF1+) and astrocytes in this region and plays paramount roles in excitatory synaptic plasticity in the adult brain. Notably, we found that selective deletion of mGluR5 in VMH SF1+ neurons significantly impaired glycemic control and lipid metabolism without affecting body weight in mutant (mGluR5f/f:SF1-cre) female but not in male mice. Thus, we hypothesize that mGluR5 acts downstream of BDNF to mediate glucose and lipid homeostasis in a weight-independent and sex-specific manner by elevating the excitatory tone of SF1+ neurons. Aim 1 will test the hypothesis that sex-specific effects of mGluR5 in SF-1+ neurons involve functional interactions with estrogen receptors (ER). Aim 2 consists of anatomical, electrophysiological and molecular studies ascertaining the sex-specific role of mGluR5 regulating activity of SF1+ neurons, Aim 3 will define molecular mechanisms in SF1+ neurons governed by ER-mGluR5 interactions to control neuronal activity and glucose and lipid homeostasis and Aim 4 will test whether effects of BDNF on metabolic function are mediated by mGluR5-ER functional interactions in females. In aggregate, these investigations will inform novel mechanisms mediating glucose homeostasis and new avenues to tackle diabetes and its associated medical complications. In particular, it will inform the higher risk of insulin resistance and metabolic disorders reported in post menopausal women.