White adipose tissue (WAT) is specialized for the storage of triacylglycerol (TAG) to release fatty acids (FA) into the circulation for other organs to use as an energy source. In contrast, brown adipose tissue (BAT) uses FA to activate uncoupling protein 1 (UCP1) for non-shivering thermogenesis to dissipate energy as heat. In human infants, there is an abundance of BAT that eventually converts into WAT with age. However, the recent discovery of presence of functional BAT in adults has generated renewed interest in the study of BAT for potential prevention and treatment of obesity. Nevertheless, the process and underlying mechanisms for the maintenance of BAT phenotype or the conversion of BAT to WAT are not understood. Here, we present preliminary data that show a previously unknown role for desnutrin, the major adipose TAG hydrolase in BAT phenotype and function. Namely, adipose-specific ablation of desnutrin in mice causes a striking conversion of BAT to a WAT-like tissue, repressing UCP-1 and other BAT-enriched genes and changing mitochondrial morphology, severely impairing thermogenesis. In contrast, overexpression of desnutrin in adipose tissue increases UCP1 expression and thermogenesis. To explain these observations, we hypothesize that desnutrin- catalyzed lipolysis is required for maintaining BAT phenotype and function. Our studies will elucidate the mechanisms underlying adipose tissue plasticity reflected in the interconversion of BAT and WAT and the signaling pathway for desnutrin's essential role in maintaining BAT phenotype and function. The three specific aims proposed are: 1. to determine the requirement of desnutrin-catalyzed lipolysis for maintaining BAT phenotype and function. 2. To examine the role of AMP-activated protein kinase in regulating BAT function through phosphorylation and activation of desnutrin. 3. To study PPARa as a downstream effector of desnutrin-catalyzed lipolysis for maintaining BAT phenotype and function. These studies will clearly demonstrate the critical role that desnutrin-catalyzed lipolysis plays in the maintaining the function and phenotype of BAT. This research will highlight the involvement of AMP-activated protein kinase in activating desnutrin, as well as the participation of PPARa as a downstream target of desnutrin-catalyzed lipolysis, in maintaining functional BAT. Our findings may provide underlying mechanisms for the well-documented increase in adaptive thermogenic capacity upon cold exposure. Understanding this process may provide future therapeutic targets to control obesity by maintenance or induction of BAT in adults.

Public Health Relevance

Of the two types of adipose tissue, white adipose tissue stores energy as fat to increase adiposity, whereas brown adipose tissue uses fat to dissipate as heat for thermogenesis and may decrease adiposity. This research is directed toward understanding the process of conversion between white and brown adipose tissue controlled by an enzyme that starts breakdown of fat. Understanding the mechanism and signaling pathway for the action of this enzyme will provide us novel targets to develop strategies to control obesity and its related diseases such as diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK093928-02
Application #
8399708
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
2011-12-12
Project End
2015-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
2
Fiscal Year
2013
Total Cost
$309,382
Indirect Cost
$99,494
Name
University of California Berkeley
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Tang, Tianyi; Abbott, Marcia J; Ahmadian, Maryam et al. (2013) Desnutrin/ATGL activates PPAR? to promote mitochondrial function for insulin secretion in islet ? cells. Cell Metab 18:883-95