Photoperiodic Control of Obesity

西伯利亚仓鼠在漫长的夏季（LD）中发展出自然发生的光周期诱导的肥胖症，并且在短的冬季（SD）中逆转。LD诱导的肥胖通过SNS刺激WAT而逆转，并且这些和其他数据表明，WAT SNS驱动的刺激是脂解的主要引发剂。使用逆行跨神经元病毒道示踪剂，伪狂犬病病毒（PRV），交感神经系统（SNS）流出从大脑到白色和棕色脂肪组织（WAT和BAT）的起源已被确定。使用顺行transneuronal病毒道示踪剂，H129株单纯疱疹病毒-1，WAT的中枢感觉回路已被定义。这里强调的是通过SNS的LD肥胖逆转，但操作在很大程度上独立于SD，从而与人类肥胖逆转具有更大的相关性。WAT SNS和感觉神经支配如何协调脂肪垫特异性WAT脂解和BAT产热的控制？在目标1中，使用多个PRV变体完成了对不同WAT/BAT垫的脑SNS流出投影的会聚的测试。通过将MC 4-R激动剂注射到与MC 4-R共定位的WAT/ BAT SNS流出神经元的脑部位中来测试中枢黑皮质素-4受体（MC 4-R）在WAT脂解/BAT产热中的作用。通过交感神经切除WAT垫以通过剩余的WAT垫诱导增加的SNS驱动来测试MC 4-R诱导的增加的WAT SNS驱动/脂解是否是可修改的。在目的2中，使用注射到相同WAT垫中的PRV（SNS）和H129（感觉）进行了用于促进脂解的SNS感觉反馈回路的神经解剖学测试，并通过测量响应脂解相关因素的WAT感觉神经电生理活动进行功能测试。通过选择性感觉去神经WAT垫，然后进行脂解挑战来测试感觉神经反馈对于适当WAT SNS驱动/脂解的作用。这些研究将提供新的和关键的数据，控制脂肪分解和产热在肥胖逆转。

Siberian hamsters develop a naturally-occurring, photoperiod-induced obesity in long summer days (LDs) and that is reversed by short winter days (SDs). The LD-induced obesity is reversed by SNS stimulation of WAT and these and other data show that stimulation of WAT SNS drive is the principal initiator of lipolysis. Using a retrograde transneuronal viral tract tracer, the pseudorabies virus (PRV), the origins of the sympathetic nervous system (SNS) outflow from brain to white and brown adipose tissue (WAT and BAT) have been defined. Using an anterograde transneuronal viral tract tracer, the H129 strain of the herpes simplex virus-1, the central sensory circuits from WAT have been defined. Emphasize here is on LD obesity reversal via the SNS, but the manipulations are largely independent of SDs thereby having greater relevance to human obesity reversal. How does WAT SNS and sensory innervation coordinate the control of fat pad-specific WAT lipolysis and BAT thermogenesis? In Aim 1, tests for convergence of brain SNS outflow projections to different WAT/BAT pads are done using multiple PRV variants. The role of central melanocortin-4 receptors (MC4-Rs) in WAT lipolysis/BAT thermogenesis is tested by injecting MC4-R agonist into brain sites of WAT/ BAT SNS outflow neurons co-localized with MC4-Rs. Whether MC4-R-induced increased WAT SNS drive/lipolysis is modifiable is tested by sympathectomizing WAT pads to induce increased SNS drive by the remaining WAT pads. In Aim 2, neuroanatomical tests for SNS-sensory feedback loops subserving lipolysis are done using PRV (SNS) and H129 (sensory) injected into the same WAT pads and is tested functionally by measuring WAT sensory nerve electrophysiological activity in response to lipolysis-associated factors. The role of sensory nerve feedback for appropriate WAT SNS drive/lipolysis is tested by selectively sensory denervating WAT pads followed by lipolytic challenges. These studies will provide new and critical data regarding the control of lipolysis and thermogenesis in obesity reversal.