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.

Public Health Relevance

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

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37DK035254-31
Application #
8836671
Study Section
Special Emphasis Panel (NSS)
Program Officer
Teff, Karen L
Project Start
2014-09-18
Project End
2019-07-31
Budget Start
2014-09-18
Budget End
2015-07-31
Support Year
31
Fiscal Year
2014
Total Cost
$495,895
Indirect Cost
$160,831
Name
Georgia State University
Department
Type
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302
Vaughan, Cheryl H; Zarebidaki, Eleen; Ehlen, J Christopher et al. (2014) Analysis and measurement of the sympathetic and sensory innervation of white and brown adipose tissue. Methods Enzymol 537:199-225
Ryu, Vitaly; Bartness, Timothy J (2014) Short and long sympathetic-sensory feedback loops in white fat. Am J Physiol Regul Integr Comp Physiol 306:R886-900
Nguyen, Ngoc Ly T; Randall, Jessica; Banfield, Bruce W et al. (2014) Central sympathetic innervations to visceral and subcutaneous white adipose tissue. Am J Physiol Regul Integr Comp Physiol 306:R375-86
Bartness, Timothy J; Liu, Yang; Shrestha, Yogendra B et al. (2014) Neural innervation of white adipose tissue and the control of lipolysis. Front Neuroendocrinol 35:473-93
Mul, Joram D; O'Duibhir, Eoghan; Shrestha, Yogendra B et al. (2013) Pmch-deficiency in rats is associated with normal adipocyte differentiation and lower sympathetic adipose drive. PLoS One 8:e60214
Darling, J N; Ross, A P; Bartness, T J et al. (2013) Predicting the effects of a high-energy diet on fatty liver and hippocampal-dependent memory in male rats. Obesity (Silver Spring) 21:910-7
Murphy, Keegan T; Schwartz, Gary J; Nguyen, Ngoc Ly T et al. (2013) Leptin-sensitive sensory nerves innervate white fat. Am J Physiol Endocrinol Metab 304:E1338-47
Bartness, Timothy J (2011) A potential link between dorsomedial hypothalamic nucleus NPY and energy balance. Cell Metab 13:493-4
Vaughan, C H; Shrestha, Y B; Bartness, T J (2011) Characterization of a novel melanocortin receptor-containing node in the SNS outflow circuitry to brown adipose tissue involved in thermogenesis. Brain Res 1411:17-27
Leitner, Claudia; Bartness, Timothy J (2011) An intact dorsomedial hypothalamic nucleus, but not the subzona incerta or reuniens nucleus, is necessary for short-day melatonin signal-induced responses in Siberian hamsters. Neuroendocrinology 93:29-39

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