Regulation of energy expenditure through BDNF neurons in the paraventricular hypothalamus

项目摘要/摘要 肥胖是能量摄入和能量消耗长期正平衡的结果。去寻找治疗方法 作为肥胖的靶标，这项建议侧重于阐明支配能量消耗的神经回路。在 在身体中，能量以白色脂肪组织(WAT)的形式储存，并在棕色脂肪组织(BAT)中消耗。在……下面 某些生理条件，如寒冷，能量是以热的形式从蝙蝠身上耗散的。在这些下面 在相同的条件下，Wat的某些区域可以转化为棕色脂肪细胞样细胞，表达生热基因 类似于蝙蝠，并且消耗能量。脑源性神经营养因子及其受体原肌球蛋白 受体激酶B(TrkB)在肥胖的发生发展中起着重要的作用。BDNF和TrkB的突变是 与人类和小鼠的肥胖有关。最近，我们报道了BDNF在内侧/外侧的表达。 下丘脑室旁核(PVH)的部分多突触与肩胛间棕色脂肪相连 组织(IBAT)。初步证据表明，通过激活PVHBDNF神经元的BDNF-TrkB信号可以 推动iBAT中的产热，因为PVH中BDNF的表达在冷暴露时增加。在……里面 对比性脑源性神经营养因子基因消融导致交感神经节前神经元在IBAT和 IBAT的生热功能受损。有证据表明，PVH中BDNF的表达可刺激 西雅图的生热作用。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Wat腹股沟区域(IWAT)，并在PVHBDNF神经元中发现感染。这表明一种 PVHBDNF神经元与IWAT之间的多突触联系。然而，两者之间的函数关系 BDNF-TrkB信号从PVH神经元到BAT和WAT是未知的。从长远来看，我希望探索神经 调节能量消耗的回路。我假设BDNF-TrkB信号促进适应性 Wat和Bat中的生热作用。我将用三个目的来检验这一假说：1)确认激活 PVHBDNF神经元在不影响交感神经传入心脏的情况下刺激蝙蝠适应性产热 和血管，2)阐明PVHBDNF神经元之间BDNF-TrkB信号的突触特性 和脊髓内的胆碱能交感节前神经元，以及3)确定BDNF是否表达 在PVH中，需要诱导Wat在冷暴露下发生褐变。为了实现这些目标 实验中，我将在转基因小鼠上进行病毒注射，以控制BDNF-TrkB信号。我还将使用 BAT和WAT的电生理和代谢测定。这项研究的发现将揭示出 BDNF-TrkB信号与能量消耗的重要关系。

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.