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

项目摘要 在过去的几十年里，适应性产热在棕色脂肪组织(BAT)和棕色脂肪组织中的作用 白色脂肪组织(WAT)已成为对抗人类肥胖的一种潜在的治疗途径。 然而，控制BAT和WAT的大脑电路还没有完全被绘制出来。确定神经 控制BAT和WAT褐变的途径是安全地操纵这些组织的第一步 与肥胖作斗争。由于肥胖症在女性中的患病率较高，这项研究的目标之一是检查 雌性蝙蝠产热和褐变的神经机制。仅在女性中，骨骼 下丘脑腹内侧区注射BMP8B可增加增食欲素(OX) 下丘脑下游外侧神经元的表达、BAT产热和Wat Beiging。这 BMP8B的作用可被黄体生成素受体拮抗剂阻断，依赖于循环中的卵巢雌激素 并需要抑制VMH中的细胞燃料传感器AMP激活的蛋白激酶(AMPK)。我们有 已有研究表明，雌激素可减弱葡萄糖抑制的腹外侧VMH(VlVMH)神经元的激活 在低糖状态下，通过抑制AMPK。有趣的是，雌激素受体密集聚集在vlVMH中。 此外，VlVMH内GI神经元约占神经元总数的60%。VMH之间有很高的相关性 产生一氧化氮(NO)以响应低糖的神经元和GI神经元。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。这些数据让我们假设vlVMH NNOS-GI神经元对下游激活BAT的LHox神经元具有紧张性抑制作用 生热作用和褐变作用。此外，BMP8B和雌激素一样，可以增强葡萄糖的抑制作用 在vlVMH GI神经元上，允许BAT产热和Wat Beiging增加。为了检验这一假设， 申请者将首先使用电生理记录、光遗传学和病毒辅助电路的组合 在小鼠中定位表达cre-重组酶的nNOS神经元，以检测 体外培养vlVMH、nNOS-GI和LHox神经元。根据文献，她将确定抑制剂是否 III型代谢型谷氨酸受体(MGluR)和/或GABA受体介导血管紧张素转换酶抑制作用 LHox神经元上的vlVMH nNOS-GI神经元。然后，她将在nNOS cre小鼠身上使用化学遗传学来确定 VMH nNOS神经元如何在体内调节蝙蝠的产热和WAT。最后，她会决定 BMP8B是否直接调节投射到黄体生成素的vlVMH nNOS-GI神经元。这个项目将揭开 雌激素和BMP8B促进BAT产热和WAT的神经机制 女性。这些数据对于开发治疗方法以对抗肥胖发病率的增加和 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.