More than one-third of adults were obese in 2012 with the percentage of adults that are ovenweight or obese at -67% in the USA. and the annual medical economic burden of obesity was ~$147 billion in 2008 dollars in the USA. Thus, there is a need for further basic research with clinical significance to obesity reversal therapies. The proposed work will continue the exploration ofthe roles ofthe sympathetic nervous system (SNS) and sensory system (SS) in white adipose tissue (WAT) and brown adipose tissue (BAT) function in obesity reversal. The role ofthe WAT SS is virtually unknown;therefore, we will: a) determine the physiological and behavioral responses triggered by the WAT-produced cytokine leptin, but leptin acting as a paracrine factor to increase sensory afferent activity and b) identify the lipolysis-associated stimuli that increases sensory nerve activity using electrophysiological and functional histological (c-Fos) measures for both. BAT sensory nerves will be tested for responsiveness to changes in its temperature. WAT and BAT transplants appear to correct metabolic dysregulafions suggesting potential clinical application, yet the hypothesized underlying mechanisms involve transplant-released factors without consideration of graft reinnervation now known to exist. Thus, comparisons ofthe SNS/SS innervation patterns of WAT and BAT autologous transplants using viral transneuronal tract tracing and their functional responses with their endogenous mates will be made. Glucoprivation triggers large WAT SNS drive increases, a glucocompensatory response. Other glucocompensatory responses are located in the hindbrain. The CNS sites sensitive to decreases in glucose utilization will be tested using hindbrain parenchymal injections of an anti-glucose analogue to trigger SNS drive increases and attempts to block glucoprivation-induced increases in SNS drive will be made by immunolesioning likely hindbrain sites-of-action with saporin conjugated anti- dopamine-beta hydroxylase.. Adipocyte proliferation is the hallmark of obesity, yet it is rarely studied. The mechanisms underlying the in vivo, and in vitro inhibition of white adipocyte proliferation by the SNS and its neurotransmitter norepinephrine will be determined using a primary adipocyte culture assay.
These conceptually and technically innovative topics/approaches will propel the field forward toward a deeper understanding for the role of WAT/BAT SNS/SS innervations that should have high clinical significance for therapeutic strategies to trigger obesity reversal
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