VMH SF1 neurons-originated sympathetic circuits modulating iWAT and iBAT

摘要 为了对抗肥胖及其相关的代谢合并症，精确的调节是必要的和重要的 脂肪组织功能(即脂肪分解、褐变、产热)，在能量控制中起着关键作用 平衡和葡萄糖动态平衡。下丘脑腹内侧核(VMH)是广为人知的饱腹症中枢。 防止体重增加的大脑。然而，VMH通过的确切机制和精确电路 对脂肪组织交感神经流出和功能的调节尚不完全清楚。文学和我们的 最近的研究表明，选择性刺激VMH中表达类固醇生成因子-1(SF1)的神经元迅速 增加能量消耗和发热量。我们还发现，选择性刺激VMH SF1神经元 投射到室旁丘脑(PVT)对支出和头部生成的影响最小。我们的 初步数据显示，选择性刺激VMH SF1神经元投射到PVT会增加去甲肾上腺素 腹股沟白色脂肪中(NE)含量及脂解激素敏感脂肪酶(p-HSL)的磷酸化 组织(IWAT)，刺激SF1神经元投射到吻侧中脑导水管周围灰质(RPAG)可增加去甲肾上腺素 腹股沟棕色脂肪组织的含量和温度(IBAT)。我们的结果还表明，寒冷的暴露 兴奋VMH SF1神经元的一个子集，揭示冷敏感和冷不敏感的VMH SF1神经元。因此，我们 假设存在分子上不同的VMH SF1神经元亚群，分别调节IWAT IBAT通过不同的交感神经回路发挥作用。我们重点研究了VMH SF1神经元、PVT、rPAG、 IWAT和iBAT。我们建议识别和表征SF1亚群和交感神经回路 调节IWAT或iBAT(目标1)，以确定寒冷对VMH SF1神经元和突触传递的影响 (目标2)，并确定是否减弱钙离子通透性AMPA受体(CP-AMPAR)和肿瘤坏死因子 SF1神经元中的A(TNFa)受体(TNFR)信号可以预防高脂饮食喂养的小鼠肥胖(目标3)。总的来说，我们的 以前的研究和初步结果使我们能够识别和表征SF1神经元起源 在生理和病理条件下调节IWAT或IBAT功能的交感神经回路。使用 创新的神经科学与遗传和代谢相结合的方法和技术，如中枢和 外周组织光度学，电生理学，细胞类型选择遗传，以及几个转基因小鼠系， 这项研究项目将测试几个新概念，包括以前未知的VMH SF1亚群 分别调节IWAT和iBAT功能及对冷、细胞型特异性基因的差异反应 CP-AMPAR和TNFa信号在VMH SF1神经元中的表达及其在DIO发生和发展中的作用 预防。从一系列逻辑研究中收集的信息将提供分子和电路 框架，然后允许我们和其他小组进一步研究，以进一步了解 中枢神经系统对脂肪组织功能和能量代谢以及葡萄糖稳态的调节。

Summary To combat obesity and its related metabolic comorbidities, it is necessary and significant in precisely modulating adipose tissue functions (i.e. lipolysis, beiging, thermogenesis) which play a crucial role in the control of energy balance and glucose homeostasis. The ventromedial hypothalamus (VMH) is a well-known satiety center in the brain to prevent body weight gain. However, the exact mechanisms and precise circuitry through which the VMH modulates adipose tissue sympathetic outflow and function remain incompletely understood. Literature and our recent study show that selective stimulation of neurons expressing steroidogenic factor-1 (SF1) in VMH rapidly increases energy expenditure and heat generation. We also find that selective stimulation of VMH SF1 neuron projections to paraventricular thalamus (PVT) elicits minimal effects on expenditure and head generation. Our preliminary data show that selective stimulation of VMH SF1 neuron projections to PVT increases norepinephrine (NE) contents and the phosphorylation of lipolytic hormone-sensitive lipase (p-HSL) in the inguinal white adipose tissue (iWAT), and stimulation of SF1 neuron projections to rostral periaqueductal gray (rPAG) increases NE contents and temperature in the inguinal brown adipose tissue (iBAT). Our results also show that cold exposure excites a subset of VMH SF1 neurons, revealing cold-sensitive and cold-insensitive VMH SF1 neurons. We thus hypothesize that there are molecularly distinct subsets of VMH SF1 neurons which respectively modulate iWAT and iBAT functions through different sympathetic circuits. We focus to study VMH SF1 neurons, PVT, rPAG, iWAT, and iBAT. We propose to identify and characterize SF1 subpopulations and sympathetic circuits that modulate iWAT or iBAT (Aim 1), to determine the impact of cold on VMH SF1 neurons and synapse transmission (Aim 2), and to determine if attenuating Ca2+-permeable AMPA receptor (CP-AMPAR) and tumor necrosis factor a (TNFa) receptor (TNFR) signal in SF1 neurons can prevent obesity in HFD-fed mice (Aim 3). Overall, our previous studies and preliminary results have enabled us to identify and characterize SF1 neuron-originated sympathetic circuits that modulate iWAT or iBAT functions in physiological and pathological conditions. With innovative combined neuroscience and genetic and metabolic methods and techniques such as central and peripheral tissue photometry, electrophysiology, cell-type selective genetic, and several transgenic mouse lines, this research project will test several novel concepts, including previously unknown VMH SF1 subpopulations respectively modulating iWAT and iBAT functions and differentially responding to cold, cell-type specific gene expressions, and the roles of CP-AMPAR and TNFa signals in the VMH SF1 neurons in DIO development and prevention. The information to be collected from a series of logical studies will provide a molecular and circuit framework that will then allow further studies by us and other groups to further understand the mechanisms for CNS regulations of adipose tissue function and energy metabolism as well as glucose homeostasis.