Transcriptional coactivators in metabolic signaling | Regulation of circadian metabolic rhythms | Specification and reprogramming of tissue metabolism
Metabolic syndrome has become a global epidemic that increases the risk for type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. Our laboratory is investigating the regulatory networks that control nutrient and energy metabolism in physiological and disease states, using integrated genomic, metabolomic, molecular, and mouse genetic tools. We are interested in exploring the relevance of these pathways in disease pathogenesis and their potential for therapeutic development.
Transcriptional coactivators in metabolic signaling
Transcriptional coactivators regulate chromatin states and are critical for the initiation and propagation of epigenetic signals. The PGC-1 family of coactivators serves as “hubs” that integrate nutrient and hormonal signals and regulates mitochondrial biogenesis, glucose and lipid metabolism. To define the molecular components of this regulatory network, we developed a genome-wide coactivation assay and interrogated over 1,700 human transcription factors and cofactors. These studies identified BAF60 family members as novel regulators of hepatic lipid metabolism and skeletal muscle fiber determination. Using proteomic tools, we investigated a hepatic PGC-1α transcriptional complex that controls plasma lipid homeostasis. We are currently investigating the mechanisms that regulate hepatic lipid homeostasis and the pathogenic events leading to fatty liver and its progression to non-alcoholic steatohepatitis (NASH).
Regulation of circadian metabolic rhythms
Organisms evolve diverse strategies to adapt their nutrient and energy metabolism to the light/dark cycles on the earth. While the temporal organization of metabolic activities is emerging as a fundamental aspect of energy homeostasis, how peripheral tissues integrate metabolic and timing cues still remains elusive. We previously discovered that PGC-1α integrates the biological clock with energy metabolism. PGC-1αreceives input from the circadian pacemaker and regulates rhythmic expression of core clock and metabolic genes. More recently, we found that autophagy, a process critical for nutrient homeostasis, is highly rhythmic in vivo. Our research interests in this area are to define the regulatory networks that drive metabolic rhythms and to investigate how altered circadian metabolism contributes to metabolic disease.
Specification and reprogramming of tissue metabolism
The metabolic properties of adult tissues are highly specialized, yet they exhibit a notable degree of plasticity. For example, skeletal muscle fibers differ in their oxidative capacity and contractile function, whereas adipocytes from brown and white fats are not only different in fuel metabolism, but appear to have distinct developmental origins. In response to physiological and pathological stimuli, skeletal muscle and adipose tissues undergo extensive metabolic remodeling to meet their respective functional and energetic demands. Our laboratory is investigating the mechanisms that regulate the specification of myofiber and adipocyte energy metabolism, and exploring pathways for beneficial reprogramming of their metabolic properties.