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