Photoperiodic Control of Obesity

描述(申请人提供)：肥胖已经达到流行的程度，其二次健康后果取决于白色脂肪组织(WAT)的分布，内脏脂肪增加了其发病率和严重性。我们研究西伯利亚仓鼠中自然发生的光周期肥胖，因为它与人类分享内脏和皮下Wat分布的不同调节。这种肥胖是可逆的，它是由松果体褪黑激素(MEL)调节的，将仓鼠从长的“夏天”的白天转移到短的“冬天的”白天(SDS)。SDS通过Wat的交感神经系统(SNS)神经支配引起内脏Wat比皮下Wat更大的脂解增加。我们继续扩大我们对肥胖的关注，将其他脂类刺激包括在内，并提出问题：SNS如何控制脂肪与WAT的区别动员？在目标1中，我们使用跨神经元病毒束示踪剂(伪狂犬病病毒[PRV])的多种变体来测试大脑SNS流出投射到不同的Wat垫、棕色脂肪和肾上腺髓质的收敛。我们还用PRV标记的Wat SNS流出神经元，用c-fos测试了由急性脂解刺激(冷，葡萄糖代谢)激活的神经元的共存。我们使用PRV标记的Wat SNS流出神经元的原位杂交来测试参与脂解的神经递质受体的共定位。我们通过去甲肾上腺素周转(NETO)测试这些急性脂解刺激在不同WAT垫上的SNS驱动模式的差异。在目标2中，我们测试在MEL1a受体+PRV标记的Wat SNS脑部位植入MEL受体拮抗剂是否能阻止SD诱导的脂解。我们测试SNS Wat去神经是否阻止SD诱导的Wat脂解/脂质利用基因表达的增加。我们通过体外甘露醇释放试验来检测SD诱导的SNS脂肪分解的脂肪细胞肾上腺素受体亚型。在目标3中，我们测试Wat感觉失神经是否夸大了急性(冷、葡萄糖代谢)和慢性(SDS)诱导的Wat Neto。这些研究将为Wat SNS神经支配在脂肪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.