Our lab is focused on the regulation of energy homeostasis in mammals, primarily at the level of gene transcription. This includes the problems of fat cell development, control of metabolic rates and the pathways of glucose and lipid metabolism. These studies have applications to the development of new therapies for diabetes, obesity, muscular and neurodegenerative diseases.

1. Regulation Of Fat Cell Development. We are deeply interested in the development and function of adipose cells, white, brown and beige. Our group identified the master regulator of fat development in 1994: the nuclear receptor PPARγ. Since then a major focus of our group has been to understand the pathways that control PPARγ function: its ligands, its coactivators and other transcription factors that modify its function. Since synthetic ligands to PPARγ are used clinically as anti-diabetic drugs, we are taking biochemical approaches to understanding the identity of endogenous ligands that control this receptor in vivo. We have also explored the transcriptional control of brown fat differentiation; this led to the identification of a futile cycle of creatine phosphorylation and dephosphoryation as being a critical component of adaptive thermogenesis. We have recently identified the critical creatine kinase (CKB) and creatine phosphate hydrolase (TNAP) involved in this pathway.

2. 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, the PGC-1 coactivators have illustrated the regulation of critical metabolic programs is controlled largely via transcriptional coactivation. Brown fat-mediated thermogenesis muscle fiber type switching and hepatic gluconeogenesis are all induced via expression of PGC-α, then docks on a variety of transcription factor targets. PGC1α mRNA undergoes much control at the level of mRNA translation and we are currently exploring factors involved in this process.

3. Function and Regulation of Irisin. Irisin is a PGC1α-dependent myokine secreted into the blood of mice and humans. It influences bone development and osteoporosis in female mice; its function in motor nerves and the CNS is under study in our lab and others. We are currently studying the effects of irisin in muscular dystrophies, where diabetes is common and in ALS.