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.
Obesity reversal is poorly understood, but decreases in visceral fat especially improves health. Because fat depots do not decrease in size uniformly, understanding the mechanisms controlling the breakdown of stored lipid in each fat depot is critical. Here we uniquely test the roles of brain connections to fat and conversely fat connections to brain via sympathetic and sensory nerves, respectively, in this process using a naturally-occurring model of seasonal obesity.
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