Photoperiodic Control of Obesity

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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.