Glucose inhibited neurons in the control of brown and white adipose tissue

项目摘要 在过去的几十年里，棕色脂肪组织（BAT）和棕色脂肪组织中的适应性产热作用 白色脂肪组织（WAT）已经成为对抗人类肥胖的潜在治疗途径。 然而，控制BAT和WAT的大脑回路尚未完全映射。确定神经 控制BAT和WAT的通路是安全操纵这些组织的第一步， 与肥胖作斗争由于肥胖在女性中的患病率较高，因此本研究的目的之一是检查 雌性BAT产热和WAT染色的神经机制仅在女性中，骨 在下丘脑腹内侧（VMH）注射形态发生蛋白8B（BMP 8B）增加食欲素（OX） 下游外侧下丘脑（LH）神经元中的表达，BAT产热和WAT染色。这 BMP 8B的作用可被LH OX受体拮抗剂阻断，依赖于循环卵巢雌激素 并且需要抑制VMH中的细胞燃料传感器AMP活化蛋白激酶（AMPK）。我们有 已经表明雌激素减弱腹外侧VMH（vlVMH）葡萄糖抑制（GI）神经元的激活 通过抑制AMPK来降低血糖。有趣的是，雌激素受体密集地聚集在vlVMH中。 此外，GI神经元占vlVMH中神经元的约60%。VMH与神经功能缺损程度之间存在高度相关性， 产生一氧化氮（NO）的神经元对低葡萄糖和GI神经元的反应。此外，VMH GI神经元 需要神经元型一氧化氮合酶（nNOS）来感知葡萄糖。这些数据使我们假设vlVMH nNOS-GI神经元对激活BAT的下游LH OX神经元施加紧张性抑制 产热和WAT beiging。此外，BMP 8B，像雌激素一样，增加葡萄糖的抑制作用， 对vlVMH GI神经元的作用，从而允许BAT产热和WAT beiging增加。为了验证这一假设， 申请人将首先使用电生理记录、光遗传学和病毒辅助电路的组合 在nNOS神经元中表达cre重组酶的小鼠中作图，以检查 vlVMH nNOS-GI和LH-OX神经元体外。根据文献，她将确定是否有抑制剂， III组代谢型谷氨酸受体（mGluR）和/或GABA受体介导的抑制作用 vlVMH nNOS-GI神经元对LH OX神经元的影响。然后，她将在nNOS cre小鼠中使用化学遗传学来确定 VMH nNOS神经元如何调节BAT产热和WAT染色最后，她将决定 BMP 8B是否直接调节投射到LH的vlVMH nNOS-GI神经元。该项目将揭示 雌激素和BMP 8B增加BAT产热和WAT beiging的神经机制， 女性这些数据对于开发治疗方法以对抗肥胖症发病率的增加非常重要， 绝经后妇女的代谢紊乱。

Project Summary Over the past several decades a role for adaptive thermogenesis in brown adipose tissue (BAT) and beiging of white adipose tissue (WAT) has emerged as a potential therapeutic avenue to combat human obesity. However, the brain circuitry that controls BAT and WAT has not been fully mapped. Determining the neural pathway that controls both BAT and WAT beiging is the first step toward safely manipulating these tissues to combat obesity. As obesity has a higher prevalence in females, it is one goal of this study to examine the neural mechanism underlying BAT thermogenesis and WAT beiging in females. In females only, bone morphogenic protein 8B (BMP8B) injection in the ventromedial hypothalamus (VMH) increased orexin (OX) expression in downstream lateral hypothalamic (LH) neurons, BAT thermogenesis and WAT beiging. This effect of BMP8B was blocked by LH OX receptor antagonists, was dependent on circulating ovarian estrogens and required inhibition of the cellular fuel sensor AMP-activated protein kinase (AMPK) in the VMH. We have already shown that estrogen blunts activation of the ventrolateral VMH (vlVMH) glucose inhibited (GI) neurons in low glucose by inhibiting AMPK. Interestingly, estrogen receptors are densely clustered in the vlVMH. Further, GI neurons make up ~60% of the neurons in the vlVMH. There is a high correlation between VMH neurons that produce nitric oxide (NO) in response to low glucose and GI neurons. Moreover, VMH GI neurons require neuronal nitric oxide synthase (nNOS) to sense glucose. These data lead us to hypothesize that vlVMH nNOS-GI neurons exert a tonic inhibition of the downstream LH OX neurons which activate BAT thermogenesis and WAT beiging. Further, that BMP8B, like estrogen, increases the inhibitory effect of glucose on vlVMH GI neurons allowing BAT thermogenesis and WAT beiging to increase. To test this hypothesis, the applicant will first use a combination of electrophysiological recordings, optogenetics and virally assisted circuit mapping in mice expressing cre-recombinase in nNOS neurons to examine the neural connection between the vlVMH nNOS-GI and LH OX neurons in vitro. Based on the literature she will determine whether inhibitors of group III metabotropic glutamate receptors (mGluR) and/or GABA receptors mediate the inhibitory effect of vlVMH nNOS-GI neurons on LH OX neurons. She will then use chemogenetics in nNOS cre mice to determine how VMH nNOS neurons regulate BAT thermogenesis and WAT beiging in vivo. Finally, she will determine whether BMP8B directly regulates vlVMH nNOS-GI neurons which project to the LH. This project will uncover the neural mechanisms by which estrogen and BMP8B increase BAT thermogenesis and WAT beiging in females. These data are important for developing therapies to counter the increased incidence of obesity and metabolic disorders in post-menopausal women.