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.
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.
| Kim, Sun-Joong; Tang, Tianyi; Abbott, Marcia et al. (2016) AMPK Phosphorylates Desnutrin/ATGL and Hormone-Sensitive Lipase To Regulate Lipolysis and Fatty Acid Oxidation within Adipose Tissue. Mol Cell Biol 36:1961-76 |
| Perry, Rachel J; Camporez, João-Paulo G; Kursawe, Romy et al. (2015) Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell 160:745-758 |
| 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 |
| Ahmadian, Maryam; Abbott, Marcia J; Tang, Tianyi et al. (2011) Desnutrin/ATGL is regulated by AMPK and is required for a brown adipose phenotype. Cell Metab 13:739-48 |
| Ahmadian, Maryam; Wang, Yuhui; Sul, Hei Sook (2010) Lipolysis in adipocytes. Int J Biochem Cell Biol 42:555-9 |
| Abbott, Marcia J; Tang, Tianyi; Sul, Hei Sook (2010) The Role of Phospholipase A(2)-derived Mediators in Obesity. Drug Discov Today Dis Mech 7:e213-e218 |
| Ahmadian, Maryam; Duncan, Robin E; Sul, Hei Sook (2009) The skinny on fat: lipolysis and fatty acid utilization in adipocytes. Trends Endocrinol Metab 20:424-8 |
| Jaworski, Kathy; Ahmadian, Maryam; Duncan, Robin E et al. (2009) AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency. Nat Med 15:159-68 |
