Photoperiodic Control of Obesity

描述（由申请方提供）：肥胖已达到流行比例，其继发性健康后果取决于白色脂肪组织（WAT）分布，内脏脂肪增加了其发生率和严重程度。我们研究了西伯利亚仓鼠自然发生的光周期性肥胖，因为它与人类共享内脏与皮下WAT分布的差异调节。这种肥胖是可逆的移动仓鼠从漫长的'夏季样'到短'冬季样'天（SD），并介导的松果体褪黑激素（MEL）。SD通过WAT的交感神经系统（SNS）神经支配触发内脏与皮下WAT的脂解增加。我们继续并扩大我们对这种肥胖的关注，包括其他脂解刺激，并问：SNS如何控制WAT的脂质差异动员？在目标1中，我们使用跨神经元病毒道示踪剂（伪狂犬病病毒[PRV]）的多种变体测试大脑SNS流出投射到不同WAT垫、棕色脂肪和肾上腺髓质的会聚。我们还测试了共定位的神经元激活的急性脂解刺激（冷，glucoprivation）使用c-fos，PRV标记的WAT SNS流出神经元。我们测试共定位的神经递质受体参与脂解，使用原位杂交PRV标记的WAT SNS流出神经元。我们通过去甲肾上腺素周转（NETO）测试这些急性脂解刺激在WAT垫上SNS驱动模式的差异。在目的2中，我们测试在MEL 1a受体+PRV标记的WAT SNS脑部位植入MEL受体拮抗剂是否阻断SD诱导的脂解。我们测试SNS WAT去神经阻断SD诱导的WAT脂解/脂质利用基因表达的增加。我们测试的脂肪细胞肾上腺素受体亚型的基础SD诱导SNS脂解在体外甘油释放测定分离的脂肪细胞。在目标3中，我们测试WAT感觉去神经支配是否夸大急性（冷，葡萄糖缺乏）和慢性（SD）诱导的WAT NETO。这些研究将为WAT SNS神经支配在脂质动员和肥胖逆转中的作用提供新的信息。

DESCRIPTION (provided by applicant): Obesity has reached epidemic proportions and its secondary health consequences are dependent on white adipose tissue (WAT) distribution with visceral fat increasing their incidence and severity. We study a naturally occurring photoperiodic obesity in Siberian hamsters because it shares the differential regulation of visceral vs subcutaneous WAT distribution with humans. This obesity is reversible by moving hamsters from long 'summer-like' to short 'winter-like' days (SDs) and is mediated by pineal melatonin (MEL). SDs trigger a greater increase in lipolysis by visceral vs subcutaneous WAT through the sympathetic nervous system (SNS) innervation of WAT. We continue and broaden our focus on this obesity to include other lipolytic stimuli and ask: How does the SNS control the differential mobilization of lipid from WAT? In Aim 1, we test for convergence of brain SNS outflow projections to different WAT pads, brown fat and adrenal medulla using multiple variants of a transneuronal viral tract tracer (pseudorabies virus [PRV]). We also test for colocalization of neurons activated by acute lipolytic stimuli (cold, glucoprivation) using c-fos, with PRV-labeled WAT SNS outflow neurons. We test for co-localization of neurotransmitter receptors involved in lipolysis, using in situ hybridization with PRV-labeled WAT SNS outflow neurons. We test for differences in SNS drive patterns across WAT pads by these acute lipolytic stimuli via norepinephrine turnover (NETO). In Aim 2, we test if implants of a MEL receptor antagonist at MEL1a receptor + PRV-labeled WAT SNS brain sites block SD-induced lipolysis. We test if SNS WAT denervation blocks SD-induced increases in WAT lipolysis/lipid utilization gene expression. We test which fat cell adrenoceptor subtypes underlie SD-induced SNS lipolysis by in vitro glyerol release assays in isolated adipocytes. In Aim 3, we test if WAT sensory denervation exaggerates acute- (cold, glucoprivation) and chronic (SDs)-induced WAT NETO. These studies will provide new information on the role of the WAT SNS innervation in lipid mobilization and obesity reversal.