Peripheral Neurotrophic Factors in the Regulation of Adipose Tissue Energy Expenditure

周围神经营养因子调节脂肪组织能量消耗

• 批准号: 9522965
• 负责人: Kristy L Townsend
• 金额: $ 35.65万
• 依托单位: UNIVERSITY OF MAINE ORONO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-08 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9522965
• 关键词: Address; Adipose tissue; Adrenergic Receptor; Affect; Aging; Area; Basal metabolic rate; Biology; Brain; Brain-Derived Neurotrophic Factor; Brown Fat; Cells; Chemicals; Chronic; Color; Communication; Coupled; Data; Denervation; Desire for food; Diabetes Mellitus; Eating; Energy Intake; Energy Metabolism; Exercise; Fatty acid glycerol esters; Feedback; Flow Cytometry; Genetic; Goals; Health; Human; Immune; Knock-out; Knockout Mice; Lead; Lipolysis; Maintenance; Mediating; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Microglia; Microscopy; Modeling; Mus; Myelogenous; Nerve; Nerve Growth Factors; Nerve Tissue; Neurites; Neuroimmune; Neuromuscular Junction; Neuronal Plasticity; Neurons; Neuropathy; Obesity; Operative Surgical Procedures; Pathway interactions; Peripheral; Peripheral Nerves; Peripheral Nervous System; Phagocytes; Phagocytosis; Phenotype; Physical activity; Population; Process; Protocols documentation; Regulation; Reporter; Research; Role; Signal Transduction; Source; Spinal nerve structure; Stimulus; Synapses; Techniques; Thermogenesis; Tissues; Treatment Factor; Vertebral column; Weight; adiponectin; axonal degeneration; base; brain morphology; cell type; energy balance; experience; experimental study; innovation; knockout animal; lipid biosynthesis; macrophage; mind control; nerve supply; neurotrophic factor; noradrenergic; novel therapeutic intervention; nutrient absorption; pandemic disease; prevent; regenerative; relating to nervous system; release factor; response; response to injury; stem; subcutaneous; synaptogenesis

In order to maintain proper energy balance and metabolic health, the body must tightly regulate the processes that control energy intake (appetite, food intake, nutrient absorption) as well as energy expenditure (physical activity, basal metabolism, thermogenesis). An important aspect of regulating energy expenditure is the transfer of signals from the brain through peripheral nerves to activate lipolysis and thermogenesis in white and brown adipose tissues, respectively. Cold-stimulation is able to increase the sympathetic innervation and activation of adipose tissues and thus increase energy expenditure through lipolysis and thermogenesis. The exact mechanisms by which cold (or other stimuli that increase energy expenditure) are able to mediate peripheral nerve plasticity are currently under-investigated and largely unclear. In the current project, we provide new evidence that white adipose tissue (WAT) undergoes increases in neural innervation after cold exposure or exercise in mice (plasticity), and reductions in neural innervation with aging or obesity/diabetes in mice and humans (neuropathy). In addition, we have demonstrated that adipose-resident immune cells are able to secrete the neurotrophic factor Brain Derived Neurotrophic Factor (BDNF), which we believe stimulates sympathetic nerve branching, neurite outgrowth, and synapse formation in order to stimulate energy-expending processes in adipose depots. Indeed, in models of adipose neuropathy such as aging, BDNF levels are significantly decreased in WAT. BDNF is well-studied in the brain, but has not been investigated for adipose tissue neurotrophic activity. We have found that BDNF is expressed in immune cells of the stromovascular fraction (SVF) of WAT, and that the secretion of BDNF increases after cold or noradrenergic stimulation. Deletion of BDNF from the myeloid lineage results in a striking and specific lack of neural innervation of adipose depots, without affecting other nerves in the brain, spinal column or neuromuscular junction. As a result of this `genetic denervation' we observed that the knock-out (KO) animals undergo a shift in energy balance that leads to increased adipose mass and lower energy expenditure, including a lack of UCP1 induction in WAT after cold exposure. We specifically hypothesize polarized macrophages in adipose tissue SVF act similarly to microglia in the brain – that is, they can be either immune cells that release nerve growth factors in response to injury or neuroplasticity needs, or they phagocytose neurites, leading to neuropathy. We have identified a population of macrophages we are calling cold-induced neuroimmune cells (CINCs) that we hypothesize secrete BDNF in response to cold/noradrenergic stimulation. In addition to investigating these mechanisms for adipose nerve plasticity and neuropathy, this project also seeks to better understand the types of nerves that innervate adipose as well as how proper innervation affects adipose tissue function, whole-body metabolism and the control of energy balance.

为了保持适当的能量平衡和代谢健康，身体必须严格调节这些过程 控制能量摄入（食欲，食物摄入，营养吸收）以及能量消耗（身体 活性、基础代谢、产热）。调节能量消耗的一个重要方面是 信号从大脑通过外周神经传递，以激活白色和 棕色脂肪组织。冷刺激能增加交感神经支配， 激活脂肪组织，从而通过脂解和产热增加能量消耗。的 冷（或其他增加能量消耗的刺激）能够介导的确切机制 周围神经可塑性目前研究不足，并且很大程度上不清楚。在目前的项目中，我们 为白色脂肪组织（WAT）在寒冷后神经支配增加提供了新的证据 暴露或运动的小鼠（可塑性），以及随着衰老或肥胖/糖尿病神经支配的减少， 小鼠和人类（神经病）。此外，我们已经证明，脂肪驻留免疫细胞是 能够分泌神经营养因子脑源性神经营养因子（BDNF），我们认为它刺激 交感神经分支，神经突生长和突触形成，以刺激能量消耗 在脂肪库中的过程。事实上，在脂肪神经病变如衰老的模型中，BDNF水平是 WAT明显下降。脑源性神经营养因子在大脑中的作用已得到充分研究，但在脂肪中的作用尚未得到研究。 组织神经营养活性。我们已经发现BDNF在基质血管的免疫细胞中表达， 脑源性神经营养因子（BDNF）的分泌在冷刺激或去甲肾上腺素能刺激后增加。 从髓系中缺失BDNF会导致神经支配的显著和特异性缺乏， 脂肪库，而不影响大脑、脊柱或神经肌肉接头中的其他神经。作为 由于这种“遗传去神经支配”，我们观察到基因敲除（KO）动物经历了能量的转变 平衡导致脂肪量增加和能量消耗降低，包括缺乏UCP 1 冷暴露后WAT的诱导。我们特别假设脂肪组织中极化的巨噬细胞 SVF的作用类似于大脑中的小胶质细胞-也就是说，它们可以是释放神经生长的免疫细胞， 这些因子可能是对损伤或神经可塑性需求的反应，或者它们吞噬神经突，导致神经病变。我们 已经鉴定出一群巨噬细胞，我们称之为冷诱导神经免疫细胞（CINCs）， 假设分泌BDNF响应冷/去甲肾上腺素能刺激。除了调查这些 脂肪神经可塑性和神经病变的机制，该项目还寻求更好地了解类型 以及适当的神经支配如何影响脂肪组织的功能，全身 代谢和能量平衡的控制。