Obesity is a significant and growing public health problem. It results from loss of energy homeostasis when increases in caloric intake are not balanced by elevated metabolic activity. Brown adipose tissue (BAT) is a potential anti-obesity organ because it is specialized to dissipate energy as heat. Circannual hibernators including ground squirrels naturally challenge conventional views of energy homeostasis by cycling between dramatic extremes of body fat storage and utilization. These animals undergo hypertrophy of BAT each year as they prepare for winter hibernation, and depend on tightly-regulated periods of non-shivering thermogenesis throughout winter hibernation. After spring emergence, BAT nearly disappears but it is re- established each fall in preparation for the next hibernation season. These temporal and functional segregations provide an extraordinary opportunity to examine and define regulatory mechanisms controlling BAT recruitment and activity. We hypothesize that hibernators employ typical mammalian mechanisms for increasing and maintaining BAT, as well as for modulating its activity. Importantly, because of the dynamics and demands of hibernation, hibernators also provide an exceptional, highly-elaborated model system in which to elucidate those mechanisms. The specific goals of the work proposed in this R21 application are to exploit an existing tissue bank, collected from a precisely-timed set of animals representing key points in the phenotypic transitions of a hibernator's year, to first: interrogate the proteome and second: the transcriptome, for qualitative and quantitative changes associated with BAT transitions. This characterization, enabled by unique advantages offered by the hibernating phenotype, will form a necessary foundation for future mechanistic studies of pathways that underlie the regulation of BAT recruitment and the reversible control of its activity, and ultimately to harness them as targets for obesity therapy.

Public Health Relevance

Project Narrative Obesity is a significant health problem in the US. It results from the loss of body weight homeostasis that occurs when incoming calories exceed daily energy requirements. Brown adipose tissue (BAT) is specialized to dissipate calories in the form of heat, thus making it an attractive target for novel approaches in obesity control. Mammalian hibernators recruit large amounts of BAT each fall in preparation for winter hibernation which then atrophies in spring. In addition, the activity of this augmented BAT is precisely controlled t orchestrate the dramatic oscillations between low and high metabolism that characterize the hibernation season. Our experiments to define the molecular alterations that underlie these phenotypic cycles in hibernation will provide novel insights to facilitate exploitation of BAT in human obesity control.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Genetics of Health and Disease Study Section (GHD)
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Haft, Carol R
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University of Colorado Denver
Schools of Medicine
United States
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Grabek, Katharine R; Diniz Behn, Cecilia; Barsh, Gregory S et al. (2015) Enhanced stability and polyadenylation of select mRNAs support rapid thermogenesis in the brown fat of a hibernator. Elife 4:
Hindle, Allyson G; Martin, Sandra L (2014) Intrinsic circannual regulation of brown adipose tissue form and function in tune with hibernation. Am J Physiol Endocrinol Metab 306:E284-99