Regulation of energy expenditure through BDNF neurons in the paraventricular hypothalamus

项目总结/摘要 肥胖是由于能量摄入和能量消耗的长期正平衡造成的。为了找到治疗 肥胖的目标，这项建议的重点是阐明神经回路，管理能量消耗。在 在人体内，能量以白色脂肪组织（WAT）的形式储存，以棕色脂肪组织（BAT）的形式消耗。下 在某些生理条件下，例如寒冷，能量以热的形式从BAT中消散。根据这些 在相同条件下，WAT的某些区域可以转化为棕色脂肪细胞样细胞，表达产热基因 类似于BAT，消耗能量。脑源性神经营养因子及其受体原肌球蛋白 受体激酶B（Trk B）在肥胖症的发展中是隐含的。BDNF和TrkB的突变是 与人类和老鼠的肥胖有关。最近，我们报道了BDNF在内侧/外侧的表达， 室旁下丘脑（PVH）的一部分多突触连接到肩胛间棕色脂肪 组织（iBAT）。初步证据表明，通过激活PVHBDNF神经元的BDNF-TrkB信号传导可以 驱动iBAT中的产热，因为PVH中的BDNF表达响应于冷暴露而增加。在 相反，Bdnf基因消融导致通往iBAT的交感神经节前神经元萎缩， iBAT中的产热受损。证据还表明，PVH中的BDNF表达刺激了 WAT产热我们通过注射伪狂犬病病毒进行了逆行跨神经元追踪 (PRV)进入腹股沟区的WAT（iWAT），并发现感染PVHBDNF神经元。这表明 PVHBDNF神经元和iWAT之间的多突触连接。然而， 从PVH神经元到BAT和WAT的BDNF-TrkB信号传导是未知的。从长远来看，我希望探索神经 调节能量消耗的电路。我假设BDNF-TrkB信号促进适应性 WAT和BAT中的产热作用。我将用三个目标来检验这一假设：1）证实 PVHBDNF神经元刺激BAT中的适应性产热而不影响心脏的交感神经输入 2）阐明PVHBDNF神经元之间BDNF-TrkB信号传导的突触特性 和胆碱能交感节前神经元，以及3）确定是否BDNF表达 在PVH中，需要诱导响应于冷暴露的WAT的布朗宁。执行这些 在实验中，我将对转基因小鼠进行病毒注射以控制BDNF-TrkB信号传导。我也会用 BAT和WAT的电生理学和代谢测量。这项研究的结果将揭示一个 BDNF-TrkB信号传导与能量消耗之间的重要关系。

PROJECT SUMMARY/ABSTRACT Obesity results from a chronic positive balance of energy intake and energy expenditure. To find therapeutic targets for obesity, this proposal focuses on elucidating neural circuits that govern energy expenditure. In the body, energy is stored as white adipose tissue (WAT) and expended in brown adipose tissue (BAT). Under certain physiological conditions such as cold, energy is dissipated from BAT in the form of heat. Under these same conditions, certain regions of WAT can convert to brown adipocyte-like cells, express thermogenic genes similar to BAT, and expend energy. Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), are implicit in the development of obesity. Mutations in BDNF and TrkB are associated with obesity in humans and mice. Recently, we reported that BDNF expression in the medial/lateral portion of the paraventricular hypothalamus (PVH) polysynaptically connects to interscapular brown adipose tissue (iBAT). Preliminary evidence suggests that BDNF-TrkB signaling via activation of PVHBDNF neurons can drive thermogenesis in iBAT because BDNF expression in the PVH increases in response to cold exposure. In contrast Bdnf gene ablation causes atrophy of sympathetic preganglionic neurons en route to iBAT and impaired thermogenesis in iBAT. Evidence also suggests that BDNF expression in the PVH stimulates thermogenesis in WAT. We performed retrograde transneuronal tracing via injection of pseudorabies virus (PRV) into the inguinal region of WAT (iWAT) and found infection in PVHBDNF neurons. This suggests a polysynaptic connection between PVHBDNF neurons and iWAT. However, the functional relationship between BDNF-TrkB signaling from PVH neurons to BAT and WAT is unknown. In the long-term I wish to explore neural circuits that regulate energy expenditure. I hypothesize that BDNF-TrkB signaling promotes adaptive thermogenesis in WAT and BAT. I will test this hypothesis with three aims: 1) to confirm that activation of PVHBDNF neurons stimulates adaptive thermogenesis in BAT without affecting sympathetic inputs to the heart and blood vessels, 2) to elucidate the synaptic properties of BDNF-TrkB signaling between PVHBDNF neurons and cholinergic sympathetic preganglionic neurons in the spinal cord, and 3) to determine if BDNF expression in the PVH is required to induce browning of WAT in response to cold exposure. To carry out these experiments, I will perform viral injections on transgenic mice to control BDNF-TrkB signaling. I will also use electrophysiology and metabolic measurements of BAT and WAT. Findings from this study will uncover an important relationship between BDNF-TrkB signaling and energy expenditure.