Peripheral Neurotrophic Factors in the Regulation of Adipose Tissue Energy Expenditure

为了保持适当的能量平衡和新陈代谢健康，身体必须严格调节这些过程。 控制能量摄入量(食欲、食物摄入量、营养吸收)和能量消耗(体力 活性、基础代谢、产热作用)。调节能源消耗的一个重要方面是 从大脑通过外周神经传递信号以激活脂肪分解和产热 棕色脂肪组织。冷刺激可增加交感神经支配和 脂肪组织的活化，从而通过脂肪分解和产热增加能量消耗。这个 寒冷(或其他增加能量消耗的刺激)能够调节的确切机制 周围神经的可塑性目前还没有得到充分的研究，而且很大程度上还不清楚。在目前的项目中，我们 提供寒冷后白色脂肪组织(WAT)神经支配增加的新证据 小鼠暴露或运动(可塑性)，以及因衰老或肥胖/糖尿病而导致的神经支配减少 老鼠和人类(神经病)。此外，我们还证明了驻留脂肪的免疫细胞是 能够分泌神经营养因子脑源性神经营养因子(BDNF)，我们认为它能刺激 交感神经分支、轴突生长和突触形成以刺激能量消耗 脂肪仓库中的加工过程。事实上，在衰老等脂肪神经病模型中，BDNF水平是 WAT显著降低。脑源性神经营养因子在大脑中得到了很好的研究，但尚未被用于脂肪研究。 组织神经营养活性。我们发现BDNF在间质血管的免疫细胞中表达。 冷刺激或去甲肾上腺素能刺激后脑源性神经营养因子的分泌增加。 脑源性神经营养因子从髓系谱系中缺失导致显著而特殊的缺乏神经支配。 脂肪储藏，不影响大脑、脊柱或神经肌肉接头的其他神经。作为一名 由于这种‘遗传去神经’，我们观察到基因敲除(KO)动物经历了能量的转移 导致脂肪质量增加和能量消耗降低的平衡，包括缺乏UCP1 冷暴露后在WAT中的诱导。我们特别假设脂肪组织中的极化巨噬细胞 Svf的作用类似于大脑中的小胶质细胞，也就是说，它们既可以是释放神经生长的免疫细胞。 反应损伤或神经可塑性需要的因素，或吞噬神经突起，导致神经病变。我们 已经确定了一组我们称之为冷诱导神经免疫细胞(CINCs)的巨噬细胞 假设冷/去甲肾上腺素能刺激后分泌BDNF。除了调查这些 脂肪神经可塑性和神经病的机制，这个项目也试图更好地了解类型 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。

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.