Differentiation of Human Tumors
Our laboratory focuses on the regulation of energy homeostasis in mammals, primarily at the level of gene transcription. Our studies - which explore the problems of fat cell development, control of metabolic rates, and the pathways of glucose and lipid metabolism - have applications to the development of new therapies for diabetes, obesity, and muscular diseases.Regulation of fat cell differentiation.In 1994, our group identified the master regulator of fat development: peroxisome proliferator-activated receptor gamma (PPAR-gamma), a nuclear receptor. Since then, a major focus of our group has been to understand the pathways that control PPAR-gamma function, its ligands and coactivators, as well as other transcription factors that modify its function. Since synthetic ligands to PPAR-gamma are used clinically as antidiabetic drugs, we are using biochemical approaches to understand the identity of endogenous ligands that control this receptor in vivo. Recently, we have begun to explore the transcriptional control of brown fat differentiation. Since brown fat cells dissipate energy as heat, this feature may provide a potential avenue into the problem of obesity and diabetes.Metabolic control through the PGC-1 coactivators. Biological control via gene transcription was thought to occur mainly through changes in amounts or activities of transcription factors. However, PPAR-gamma and its coactivators (PGC-1) have illustrated that the regulation of critical metabolic programs is controlled largely via transcriptional coactivation. Brown fat-mediated thermogenesis and hepatic gluconeogenesis are both induced through expression of PGC-1 alpha, which then docks on a variety of transcription factor targets. Most recently, we have shown that PGC-1 beta is induced in liver by diets high in saturated and trans fats, and that this coactivator is largely responsible for the subsequent elevation in blood cholesterol and triglyceride synthesis. Current projects center on how the PGC-1 coactivators function mechanically by recruiting chromatin-modifying enzymes. We are also exploring the genetic role of the PGC-1 coactivators in a variety of metabolic states, including obesity, diabetes, muscle wasting, and nerve degeneration. We are particularly interested in how the PGC-1 coactivators control a variety of mitochondrial processes, including oxidative phosphorylation and the detoxification of reactive oxygen species (ROS), which are endogenous agents involved in aging and cancer, a very important area of future research.