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

项目摘要 脑源性神经营养因子是兴奋性突触可塑性的主要调节因子， 这种神经营养因子的功能减弱与人类肥胖和代谢功能障碍有关 啮齿动物。我们发现，BDNF2L/2LCk-cre基因缺失的小鼠表现出肥胖、胰岛素 抵抗力、高血糖和血脂异常。这些发现具有重要的临床意义，因为 BdnfVal66Met变异体干扰BDNF信号转导，在人类中高度流行。上一首 研究结果表明，下丘脑腹内侧(VMH)是能量和葡萄糖的关键区域 平衡调控，是脑源性神经营养因子作用的重要部位。BDNF作用的潜在机制是 定义不明确，特别是那些独立于摄食控制的行为。这项提案将调查 代谢型谷氨酸受体5(MGluR5)介导脑源性神经营养因子对VMH神经元作用的新作用 活动和血糖控制。它源于我们的发现，mGluR5的表达显著 BDNF2L/2LCk-cre突变体的VMH降低。MGluR5在VMH中高表达，在神经元中存在 (包括SF1+)和星形胶质细胞，在兴奋性突触可塑性中起重要作用。 成人的大脑。值得注意的是，我们发现VMH SF1+神经元中mGluR5的选择性缺失显著 突变(mGluR5f/f：sf1-cre)不影响体重的血糖控制和脂代谢受损 雌性，但不在雄性小鼠身上。因此，我们假设mGluR5在BDNF下游发挥调节作用 通过提高兴奋性，以非重量和性别特异性的方式实现糖和脂的稳态 SF1+神经元的音调。目的1将验证mGluR5对SF-1+神经元的性别特异性作用的假设 涉及与雌激素受体(ER)的功能相互作用。目标2由解剖学、 电生理学和分子生物学研究确定mGluR5的性别特异性作用 SF1+神经元，目标3将定义由ER-mGluR5调控的SF1+神经元的分子机制 控制神经元活动和糖脂平衡的相互作用和目标4将测试 BDNF对代谢功能的影响是通过女性体内mGluR5-ER功能相互作用来实现的。在……里面 总而言之，这些研究将揭示调节葡萄糖稳态的新机制和新的 解决糖尿病及其相关医疗并发症的途径。特别是，它将通知上级 绝经后妇女发生胰岛素抵抗和代谢紊乱的风险报告。

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.