VMH SF1 neurons-originated sympathetic circuits modulating iWAT and iBAT

VMH SF1 神经元起源的交感神经回路调节 iWAT 和 iBAT

• 批准号: 10635521
• 负责人: Yunlei Yang
• 金额: $ 45.33万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-17 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10635521
• 关键词: AMPA Receptors; Acclimatization; Action Potentials; Acute; Adipose tissue; Brain; Brown Fat; Central Nervous System; Cytoplasm; Data; Development; Electrophysiology (science); Energy Metabolism; Expenditure; Gene Expression; Generations; Genes; Genetic; Genetic Transcription; Glucose; Glutamate Receptor; Head; High Fat Diet; Hypothalamic structure; Insulin; Label; Leptin; Lipolysis; Literature; Logic; Maps; Mediating; Messenger RNA; Metabolic; Methods; Molecular; Mus; Neurons; Neurosciences; Neurotransmitter Receptor; Norepinephrine; Obesity; Pathologic; Pathway interactions; Peripheral; Permeability; Phosphorylation; Photometry; Physiological; Play; Population; Probability; Receptor Signaling; Regulation; Research Project Grants; Role; SF1; Series; Signal Transduction; Site; Slice; Synapses; TNF gene; TNFRSF1A gene; Techniques; Temperature; Testing; Thalamic structure; Therapeutic Intervention; Thermogenesis; Time; Tissues; Transgenic Mice; Tumor Necrosis Factor Receptor; Weight Gain; adeno-associated viral vector; blood glucose regulation; cell type; combat; comorbidity; diet-induced obesity; energy balance; enhancing factor; excitotoxicity; experimental study; factor A; feeding; glucose tolerance; inflammatory marker; innovation; knock-down; midbrain central gray substance; mind control; neural circuit; neurotransmitter release; novel; obesity development; obesity prevention; prevent; receptor; receptor expression; satiety center; single-cell RNA sequencing; sterol esterase; transmission process; treatment strategy

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.

概括 为了打击肥胖及其相关的代谢合并症，它在精确调节方面是必要和重要的 脂肪组织功能（即脂解，蛋白质，热生成），在控制能量中起着至关重要的作用 平衡和葡萄糖稳态。腹侧下丘脑（VMH）是众所周知的饱腹感中心 大脑以防止体重增加。但是，VMH的确切机制和精确电路 调节脂肪组织交感神经流出和功能仍然不完全理解。文学和我们的 最近的研究表明，在VMH中迅速表达类固醇生成因子1（SF1）的神经元的选择性刺激 增加能量消耗和热量产生。我们还发现VMH SF1神经元的选择性刺激 对室丘脑丘脑（PVT）的预测会引起对支出和头部产生的最小影响。我们的 初步数据表明，对PVT的VMH SF1神经元投影的选择性刺激会增加去甲肾上腺素 （NE）腹股沟白脂肪中脂溶性激素敏感脂肪酶（P-HSL）的含量和磷酸化 组织（IWAT），并刺激SF1神经元投影对尾骨周围灰色（RPAG）增加NE 腹股沟棕色脂肪组织（IBAT）中的含量和温度。我们的结果还表明寒冷暴露 激发VMH SF1神经元的一部分，揭示了冷敏感和感冒敏感的VMH SF1神经元。我们这样 假设存在分子不同的VMH SF1神经元的子集，它们分别调节IWAT 和IBAT通过不同的交感神经函数。我们专注于研究VMH SF1神经元，PVT，RPAG， IWAT和IBAT。我们建议识别和表征SF1的亚群和交感神经电路 调节IWAT或IBAT（AIM 1），以确定CORD对VMH SF1神经元和突触传播的影响 （AIM 2），并确定是否衰减Ca2+可渗透AMPA受体（CP-AMPAR）和肿瘤坏死因子 SF1神经元中的A（TNFA）受体（TNFR）信号可以防止HFD喂养的小鼠的肥胖症（AIM 3）。总体而言，我们的 先前的研究和初步结果使我们能够识别和表征SF1神经元灌注的 在生理和病理条件下调节IWAT或IBAT功能的交感神经。和 创新的联合神经科学以及遗传和代谢方法和技术，例如中央和技术 外周组织光度法，电生理学，细胞类型选择性遗传和几种转基因小鼠系， 该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函数，并差异地响应冷细胞类型的特异性基因 表达式以及CP-Ampar和TNFA信号在VMH SF1神经元中的作用在DIO发育和 预防。从一系列逻辑研究中收集的信息将提供分子和电路 框架将允许我们和其他群体的进一步研究进一步了解 CNS脂肪组织功能和能量代谢以及葡萄糖稳态的法规。