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

基本信息

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
项目类别：
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

项目摘要

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.

概括为了对抗肥胖及其相关的代谢合并症，精确调控是必要且重要的。脂肪组织功能（即脂肪分解、米色、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。下丘脑腹内侧区（VMH）是众所周知的饱腹感中枢。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不完全清楚。文学与我们最近的研究表明，选择性刺激 VMH 中快速表达类固醇生成因子 1 (SF1) 的神经元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室旁丘脑（PVT）的投射对支出和头部产生的影响最小。我们的初步数据表明，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（NE）含量和脂肪分解激素敏感脂肪酶（p-HSL）的磷酸化组织 (iWAT) 和刺激 SF1 神经元投射到导水管周围灰质 (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，冷暴露激发 VMH SF1 神经元的子集，揭示冷敏感和冷不敏感的 VMH SF1 神经元。我们因此假设 VMH SF1 神经元存在分子上不同的子集，分别调节 iWAT iBAT 和 iBAT 通过不同的交感神经回路发挥作用。我们重点研究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 Ca2+ 通透性 AMPA 受体 (CP-AMPAR) 和肿瘤坏死因子 SF1 神经元中的 (TNFa) 受体 (TNFR) 信号可以预防 HFD 喂养小鼠的肥胖（目标 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。和创新的神经科学与遗传和代谢相结合的方法和技术，例如中枢和外周组织光度测定、电生理学、细胞类型选择性遗传和几种转基因小鼠品系，该研究项目将测试几个新颖的概念，包括以前未知的 VMH SF1 亚群分别调节 iWAT 和 iBAT 功能并对寒冷、细胞类型特异性基因做出差异反应 VMH SF1 神经元中 CP-AMPAR 和 TNFa 信号的表达以及在 DIO 发育和发育过程中的作用预防。从一系列逻辑研究中收集的信息将提供分子和电路框架，然后将允许我们和其他团体进行进一步的研究，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。