While a role for adenosine monophosphate activated protein kinase (AMPK) in regulating body energy balance via effects in non-adipose tissues has gained acceptance, little is known about the biological function of AMPK in white and brown adipose tissues. The proposed studies will test two hypotheses, the first being that adrenergic signaling regulates AMPK activity in white adipose tissue, which in turn plays a role in controlling white adipocyte insulin sensitivity and adipokine production. The second hypothesis is that AMPK contributes to the regulation of body weight and temperature by controlling the thermogenic potential and amount of non-shivering thermogenesis in brown adipose. To test these hypotheses, three specific aims will be accomplished. First, the adrenergic receptor sub-type(s) necessary and sufficient to upregulate 11 AMPK activity in white adipose tissue, as well as the cell type(s) in which this occurs, will be determined. This will be done in vivo by exposing wildtype and 23-adrenergic receptor knockout mice to 14 days of cold exposure or adrenergic receptor agonists administered via micro-osmotic pumps, and fractionating the white adipose tissue using differential centrifugation.
The second aim i s to determine what role sympathetic modulation of 11 AMPK activity has in """"""""healthful"""""""" and """"""""harmful"""""""" remodeling of white adipose tissue. In mice, the extent to which 23-adrenergic induced healthful remodeling of WAT occurs in AMPK knockout mice will be determined. In metabolic syndrome patients and age/sex matched controls, the hypothesis that desensitization of adrenergic signaling in white adipocytes is associated with a downregulation of 11 AMPK activity will be tested.
The third aim i s to test the hypothesis that chronic weight gain increases caloric expenditure of BAT via an AMPK-mediated increase in brown adipocyte mitochondrial biogenesis. This will be tested in wildtype and 11 AMPK knockout mice in vivo, as well as in vitro using pharmacological activation and inhibition of 11 AMPK in primary cultures of brown adipocytes. The long term goal of this research is to manipulate the amount, and """"""""health"""""""" of white adipose tissue by targeting the AMPK signaling system in white and brown adipocytes.

Public Health Relevance

Efforts to combat the """"""""obesity epidemic"""""""" by encouraging exercise and dieting have been largely unsuccessful. Our studies examine a way of metabolizing calories into heat instead of storing them as fat, and the possibility that the """"""""health"""""""" of fat is regulated by a branch of the autonomic nervous system. ? ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Haft, Carol R
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University of Wisconsin Madison
Internal Medicine/Medicine
Schools of Medicine
United States
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Lindholm, Christopher R; Ertel, Rebecca L; Bauwens, Jake D et al. (2013) A high-fat diet decreases AMPK activity in multiple tissues in the absence of hyperglycemia or systemic inflammation in rats. J Physiol Biochem 69:165-75
Schmuck, Eric G; Mulligan, Jacob D; Saupe, Kurt W (2011) Caloric restriction attenuates the age-associated increase of adipose-derived stem cells but further reduces their proliferative capacity. Age (Dordr) 33:107-18
Bauwens, Jake D; Schmuck, Eric G; Lindholm, Christopher R et al. (2011) Cold tolerance, cold-induced hyperphagia, and nonshivering thermogenesis are normal in ??-AMPK-/- mice. Am J Physiol Regul Integr Comp Physiol 301:R473-83