Sympathetic Regulation of AMPK in the control of non-shivering thermogenesis

University Of Wisconsin-Madison, Madison WI

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Abstract

DESCRIPTION (provided by applicant): 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 is 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 is 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.