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.

总结 为了对抗肥胖及其相关的代谢性共病，精确调节 脂肪组织的功能（即脂解，beiging，产热），在能量控制中起着至关重要的作用 平衡和葡萄糖稳态。腹内侧下丘脑（VMH）是一个众所周知的饱腹中枢， 大脑，以防止体重增加。然而，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清楚。文学与我们 最近的研究表明，选择性刺激VMH中表达类固醇生成因子-1（SF-1）的神经元， 增加能量消耗和热量产生。我们还发现选择性刺激VMH SF 1神经元 投射到室旁丘脑（PVT）对消耗和头部生成的影响最小。我们 初步数据显示，选择性刺激VMH SF 1神经元投射到PVT增加去甲肾上腺素 (NE)腹股沟白色脂肪中脂解酶敏感性脂肪酶（p-HSL）的含量和磷酸化 组织（iWAT），并且刺激SF 1神经元投射到头端导水管周围灰质（rPAG）增加NE 腹股沟棕色脂肪组织（iBAT）的含量和温度。我们的研究结果还表明， 兴奋VMH SF 1神经元的一个子集，揭示冷敏感和冷不敏感VMH SF 1神经元。我们因此 假设存在分别调节iWAT分子上不同的VMH SF 1神经元亚群 iBAT通过不同的交感神经回路发挥作用。我们重点研究VMH SF 1神经元、PVT、rPAG、 iWAT和iBAT。我们建议识别和表征SF 1亚群和交感神经回路， 调节iWAT或iBAT（目的1），以确定冷对VMH SF 1神经元和突触传递的影响 (Aim 2），并确定是否减弱钙渗透性AMPA受体（CP-AMPAR）和肿瘤坏死因子 SF 1神经元中的a（TNFa）受体（TNFR）信号可以预防喂食HFD的小鼠的肥胖（Aim 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SF 1神经元源性 交感神经回路在生理和病理条件下调节iWAT或iBAT功能。与 创新的神经科学和遗传与代谢方法和技术相结合， 外周组织光度学、电生理学、细胞类型选择遗传学，以及几种转基因小鼠品系， 该研究项目将测试几个新概念，包括以前未知的VMH SF 1亚群 分别调节iWAT和iBAT功能，并对冷细胞类型特异性基因 表达，以及CP-AMPAR和TNF α信号在DIO发育中VMH SF 1神经元中的作用， 预防从一系列逻辑研究中收集的信息将提供一个分子和电路 框架，然后将允许我们和其他团体进一步研究，以进一步了解 CNS调节脂肪组织功能和能量代谢以及葡萄糖稳态。