Bruce M. Spiegelman
Department of Cell Biology
CLS Building 11145
3 Blackfan Circle
Boston, MA 02115
Lab Members: 14 postdoctoral fellows, 1 graduate student
Regulation of Fat Cell Differentiation. Our group identified the master regulator of fat development in 1994: the nuclear receptor PPARg. Since then a major focus of our group has been to understand the pathways that control PPARg function: its ligands, its coactivators and other transcription factors that modify its function. Since synthetic ligands to PPARg 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. Recently, we have made progress on the transcriptional control of brown fat differentiation, including identification of the key regulator of brown fat development PRDM16. Since brown fat cells dissipate energy as heat, this is an interesting potential avenue into the obesity/diabetes problem.
We have also become interested on covalent modifications of PPARg. We have recently shown that anti-diabetes drugs that bind to PPARg work not as agonists, but by blocking the phosphorylation of PPARg by cdk5.
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-1coactivators have illustrated the regulation of critical metabolic programs is controlled largely via transcriptional coactivation. Brown fat-mediated thermogenesis and hepatic gluconeogenesis are both induced via expression of PGC-1α which then docks on a variety of transcription factor targets. Most recently, we have shown that PGC-1β is induced in liver by diets high in saturated and trans fats, and this coactivator is largely responsible for the subsequent elevation in blood cholesterol and triglyceride synthesis. Current projects are centered on how the PGC-1 coactivators function mechanically via recruiting chromatin modifying enzymes. We are also exploring the genetic role of the PGC-1’s in a variety of metabolic states, including obesity, diabetes, muscle wasting and nerve degeneration. Lastly, 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). ROS are endogenous agents involved in aging and cancer, and this is a very important future area.
St. Pierre J, Drori D, Uldry M, Silvaggi J, Rhee J, Jaeger S, Handschin C, Zheng K, Lin J, Yang W, Simon DK, Bachoo R and Spiegelman BM. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 2006; 127:397-402.
Seale P, Kajimura S, Yang W, Chin S, Rohas L, Uldry M, Tavernier G, Langin D and Spiegelman BM. Transcriptional control of brown fat determination by PRDM16. Cell Metabolism 2007; 6:38-54.
Arany, Z, Foo S-Y, Ma Y, Ruas JL, Bommi-Reddy A, Girnun G, Cooper M, Laznik D, Rangwala S, Rosenzweig A and Spiegelman BM. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1α. Nature 2008; 451:1008-1012.
Seale P, Bjork B, Yang W, Kajimura S, Kuang S, Scime A, Devarakonda K, Chin S, Conroe H, Erdjument-Bromage H, Tempst P, Rucnicki MA, Beier DR and Spiegelman BM. PRDM16 controls a brown fat/skeletal muscle switch. Nature 2008; 454:961-967.
Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV, Gygi SP, Spiegelman BM. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP β transcriptional complex. Nature 2009; 460(7259):1154-1158.
Choi JH, Banks AS, Estall JL, Kajimura S, Bostrom P, Laznik D, Ruas JR, Chalmers MJ, Kamenecka TM, Bluher M, Griffin PR, Spiegelman BM. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARg by Cdk5. Nature 2010; 466:451-456.
Choi JH, Banks AS, Kamenecka TM, Busby SA, Chalmers MJ, Kumar N, Kuruvilla DS, Shin Y, He Y, Bruning JB, Marciano DP, Cameron MD, Laznik D, Jurczak MJ, Schürer SC, Vidović D, Shulman GI, Spiegelman BM and Griffin PR. Anti-Diabetic Actions of a Non-Agonist PPARg Ligand Blocking Cdk5-Mediated Phosphorylation. Nature 2011; In Press
For a complete listing of publications click here.
Last Update: 7/26/2012