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

mGluR5 在 VMH 中影响葡萄糖稳态的性别特异性作用

基本信息

批准号：
9769014
负责人：
Maribel Rios
金额：
$ 48.8万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-14 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9769014
关键词：
Adult Affect Affinity Chromatography Anatomy Astrocytes Biochemical Body Weight Brain Brain region Brain-Derived Neurotrophic Factor Cells Clinical Coupled Diabetes Mellitus Disease Electrophysiology (science)Epidemic Equilibrium Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens Exhibits FOS gene Female Functional disorder GTP-Binding Proteins Genetic Transcription Genomics Glucose Glucose Intolerance Glutamate Receptor Homeostasis Human Hyperglycemia Hyperphagia Hypothalamic structure Impairment Instruction Insulin Resistance Investigation Link Lipids Mediating Membrane Metabolic Metabolic Diseases Metabolic dysfunction Methods Molecular Mus Mutant Strains Mice Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Obesity Pilot Projects Play Postmenopause Proteins Regulation Reporting Ribosomes Rodent Role SF1 Signal Transduction Site Specificity Synapses Synaptic plasticity Testing Translating Translations United States Variant Weight Weight Gain Weight maintenance regimen Woman autism spectrum disorder blood glucose regulation feeding follow-up glycemic control high risk improved insight insulin sensitivity lipid metabolism male medical complication metabotropic glutamate receptor 5 mutant neuronal excitability neuronal survival neurotrophic factor non-genomic novel relating to nervous system response sex transcriptome

项目摘要

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.

项目概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，这种神经营养蛋白的功能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 耗竭 (BDNF2L/2LCk-cre) 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 BdnfVal66Met 变体会干扰 BDNF 信号传导，在人类中非常普遍。以前的研究结果表明，下丘脑腹内侧区 (VMH) 是能量和葡萄糖的关键区域平衡控制，是BDNF作用的重要部位。 BDNF 作用的机制是定义不明确，尤其是那些独立于喂养控制而行动的。该提案将调查代谢型谷氨酸受体 5 (mGluR5) 介导 BDNF 对 VMH 神经元作用的新作用活动和血糖控制。它源自我们的发现，mGluR5 表达显着 BDNF2L/2LCk-cre 突变体的 VMH 降低。 mGluR5 在 VMH 中高度表达并存在于神经元中（包括 SF1+）和该区域的星形胶质细胞，在兴奋性突触可塑性中起着至关重要的作用成人的大脑。值得注意的是，我们发现 VMH SF1+ 神经元中 mGluR5 的选择性缺失显着突变体（mGluR5f/f:SF1-cre）的血糖控制和脂质代谢受损，但不影响体重雌性小鼠，但雄性小鼠中没有。因此，我们假设 mGluR5 作用于 BDNF 下游，介导通过提高兴奋性，以与体重无关和性别特异性的方式维持葡萄糖和脂质稳态 SF1+神经元的音调。目标 1 将检验 mGluR5 对 SF-1+ 神经元的性别特异性影响这一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、电生理学和分子研究确定 mGluR5 调节活性的性别特异性作用 SF1+ 神经元，目标 3 将定义 ER-mGluR5 控制的 SF1+ 神经元的分子机制相互作用来控制神经元活动以及葡萄糖和脂质稳态，目标 4 将测试是否 BDNF 对代谢功能的影响是由女性 mGluR5-ER 功能相互作用介导的。在总的来说，这些研究将为介导葡萄糖稳态的新机制和新机制提供信息解决糖尿病及其相关医疗并发症的途径。特别是，它将通知上级据报道，绝经后妇女出现胰岛素抵抗和代谢紊乱的风险。