The long-term goal of this proposal is to elucidate the mechanisms that regulate cellular energy balance. Here, we are focusing on energy regulation in adipose tissue with a weighted focus on brown fat. Interest in brown fat bioenergetics is rapidly gaining momentum because of the recent realization that adult humans possess a significant quantity of brown fat or brown fat-like cells that may exhibit metabolically favorable "fat burning" properties. It is speculated that therapeutically increasing brown fat energy expenditure could defend against obesity. Importantly however, very little is known about the molecular signals that control energy expenditure in adipose tissue, or brown fat differentiation and function. The objective of this proposal is to test the hypothesis that the mechanistic target of rapamycin complex 2 (mTORC2) is a critical regulator of metabolism and energy expenditure in brown fat. To test this, we are taking a multidisciplinary approach utilizing genetically engineered mice, primary cell lines, and pharmacological agents to study the mechanisms by which mTORC2 and its substrates regulate energy balance in adipose tissue. Our work is yielding very interesting and unexpected preliminary findings that suggest inhibiting mTORC2 reprograms cellular metabolism and may increase brown fat activity.
In Specific Aim 1, we elucidate the mechanism by which mTORC2 reprograms metabolism.
In Specific Aim 2, we test the in vivo relevance of our hypothesis and our preliminary findings using novel mouse models.
In Specific Aim 3, we ask if pharmacologically inhibiting mTORC2 can treat pathological fat accumulation. Elucidating the metabolic regulatory circuits under mTORC2 control in brown fat will have important implications in advancing therapies targeting cellular bioenergetics.

Public Health Relevance

The prevalence of metabolic disorders in the United States is escalating, placing significant burden on the U.S. health care system. Obesity in particular is a major risk factor for type 2 diabetes, dyslipidaemias, cardiovascular disease, and cancer, and is increasing worldwide at epidemic rates. In this proposal, we investigate the molecular basis of metabolic homeostasis and energy expenditure with the goal of elucidating potential therapeutic strategies to defend against obesity by increasing cellular bioenergetics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK094004-01A1
Application #
8575320
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
2013-07-05
Project End
2018-06-30
Budget Start
2013-07-05
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$407,925
Indirect Cost
$162,925
Name
University of Massachusetts Medical School Worcester
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Sanchez-Gurmaches, Joan; Guertin, David A (2014) Adipocyte lineages: tracing back the origins of fat. Biochim Biophys Acta 1842:340-51
Sanchez-Gurmaches, Joan; Guertin, David A (2014) Adipocytes arise from multiple lineages that are heterogeneously and dynamically distributed. Nat Commun 5:4099
Hung, Chien-Min; Calejman, Camila Martinez; Sanchez-Gurmaches, Joan et al. (2014) Rictor/mTORC2 loss in the Myf5 lineage reprograms brown fat metabolism and protects mice against obesity and metabolic disease. Cell Rep 8:256-71