Adipose tissue critically regulates whole-body energy homeostasis. Mammals have two major adipose tissues: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT stores excess energy while BAT dissipates energy as heat for non-shivering thermogenesis. Some adipocytes in WAT, like brown adipocytes, express uncoupling protein-1 (UCP1), a protein that mediates heat generation by un-coupling mitochondrial respiration from ATP synthesis. This population of adipocytes is recently named ?beige? or ?brite? adipocytes. The quantity of beige adipocytes increases during cold adaptation or sympathetic activation, a process referred to as WAT browning. Mobilization of stored cellular energy for use during starvation or increased energy demand (e.g., cold adaptation) requires hydrolysis of triglycerides stored in cytosolic lipid droplets (LDs) (i.e., intracellular lipolysis). A gene critically implicated in intracellular lipolysis is CGI-58 (Comparative Gene Identification-58). In mammals, CGI-58 is ubiquitously expressed with the highest expression in fat. It interacts with LD coat proteins and activates ATGL (Adipose Triglyceride Lipase) to promote intracellular lipolysis. It was believed that intracellular lipolysis in BAT is essential for thermogenesis, but this has not been examined in vivo. We surprisingly found that mice lacking CGI-58 in BAT, i.e., BAT-specific CGI-58 knockout (BAT-KO) mice, are not cold sensitive even in the fasted state. This proposal is to define the underlying adaptive mechanisms. Our preliminary studies suggest a central hypothesis: BAT deficiency in intracellular lipolysis may reprogram BAT to take up more circulating thermogenic substrates derived from WAT lipolysis and diet and by inducing WAT thermogenesis through activation of the sympathetic nervous system. We will test this hypothesis by examining BAT thermogenesis, BAT uptake of circulating substrates, and WAT thermogenesis under different temperature, sympathetic, and nutritional states. We will also explore the origin of beige adipocytes in BAT-KO mice. Additionally, we will examine whether WAT lipolysis is required for thermogenesis and WAT browning in BAT-KO mice by using a pharmacological inhibitor of intracellular lipolysis and by simultaneous deletion of CGI-58 in both BAT and WAT (FAT-KO mice). In some experiments, we will compare adipose CGI-58 and ATGL KO mice to gain insights into other lipolytic roles of CGI-58. Furthermore, we will define how BAT lipolysis regulates energy balance, glucose disposal, insulin sensitivity, and tissue lipid metabolism. Finally, we will search for novel insights into how lipolysis deficiency augments adipose sympathetic drive. We will generally measure blood levels of lipids/adipokines/hormones, and tissue levels of lipids/gene expression to establish how CGI-58 deficiency in different adipocytes regulates lipid/energy metabolism at biochemical and molecular levels. Thermogenesis dissipates energy. Perturbation of energy balance is a hallmark of common metabolic disorders, which contribute substantially to disease morbidity and mortality. Findings from our studies hold promise of revealing novel approaches for control of overnutrition-induced metabolic disease.
Adipose tissue plays a critical role in energy storage and dissipation, dysregulation of which underlines the obesity epidemic and its associated rise of metabolic disorders. Recent rediscovery of energy-dissipating thermogenic brown adipose tissue (BAT) and beige/brite adipocytes in adult humans highlights the potential of BAT/beige adipocytes as therapeutic targets for obesity and metabolic disease. BAT thermogenesis was thought to require efficient breakdown of cytosolic triglyceride-rich lipid droplets (intracellular lipolysis), but we found that selective inactivation of CGI-58, an activator of intracellular lipolysis, in energy-dissipating adipocytes does not impair cold adaptation, and we therefore propose to define the underlying adaptive mechanisms and its metabolic consequence.