Bruce M. Spiegelman, PhD
Office phone: 617-632-3567
Preferred contact method: email
Area of ResearchDifferentiation of Human Tumors
Dana-Farber Cancer Institute
450 Brookline Avenue
Boston, MA 02215
BiographyDr. Spiegelman received his PhD in biochemistry from Princeton University in 1978, and completed postdoctoral work at Massachusetts Institute of Technology. In 1982, he joined DFCI and was promoted to professor in 1991. His research focuses on cell differentation, cellular metabolism, and genetic factors involved in obesity and diabetes.
- American Academy of Arts and Sciences, 2002
- Berson Award, American Physiology Society, 2002
- National Academy of Sciences, 2002
- Heinrich Wieland Prize in Lipid Metabolism, University of Munich, 1997
- MERIT Award, NIH, 1997
ResearchDifferentiation 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.
- Handschin C, Lin J, Rhee J, Peyer AK, Chin S, Wu PH, Meyer UA, Spiegelman BM. Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1 alpha. Cell 2005;122:505-15.
- Lin J, Yang R, Tarr PT, Wu PH, Handschin C, Li S, Yang W, Pei L, Uldry, M, Tontonoz P, Newgard CB, Spiegelman BM. Hyperlipidemic effects of dietary saturated fats mediated through PGC-1 beta coactivation of SREBP. Cell 2005;120:261-73.
- Drori S, Girnun GD, Tou L, Szwaya JD, Mueller E, Xia K, Shivdasani RA, Spiegelman BM. Hic-5 regulates an epithelial program mediated by PPAR-gamma. Genes Dev 2005;19:362-75.
- Arany Z, He H, Lin J, Hoyer K, Handschin C, Toka O, Ahmad F, Matsui T, Chin S, Wu PH, Rybkin II, Shelton JM, Manieri M, Cinti S, Schoen FJ, Bassel-Duby R, Rosenzweig A, Ingwall JS, Spiegelman BM. Transcriptional coactivator PGC-1 alpha controls the energy state and contractile function of cardiac muscle. Cell Metab 2005;1:259-71.
- Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 2005;1:361-70.
- Lin J, Wu PH, Tarr PT, Lindenberg KS, St-Pierre J, Zhang CY, Mootha VK, Jager S, Vianna CR, Reznick RM, Cui L, Manieri M, Donovan MX, Wu Z, Cooper MP, Fan MC, Rohas LM, Zavacki AM, Cinti S, Shulman GI, Lowell BB, Krainc D, Spiegelman BM. Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1 alpha null mice. Cell 2004;119:121-35.
- Mootha VK, Handschin C, Arlow D, Xie X, St Pierre, J, Sihag S, Yang W, Altshuler D, Puigserver P, Patterson N, Willy PJ, Schulman IG, Heyman RA, Lander ES, Spiegelman BM. ERRalpha and Gabpa/b specify PGC-1 alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proc Natl Acad Sci U S A 2004;101:6570-5.
- Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, Kitamura Y, Altomonte J, Dong H, Accili D, Spiegelman BM. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1 alpha interaction. Nature 2003;423:550-5.
- Rhee J, Inoue Y, Yoon JC, Puigserver P, Fan M, Gonzalez FJ, and Spiegelman BM. Regulation of hepatic fasting response by PPARgamma coactivator-1 alpha (PGC-1): requirement for hepatocyte nuclear factor 4 alpha in gluconeogenesis. Proc Natl Acad Sci U S A 2003;100:4012-7.
- Handschin C, Rhee J, Lin J, Tarr PT, Spiegelman BM. An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1 alpha expression in muscle. Proc Natl Acad Sci U S A 2003;100:7111-6.
- Uldry M, Yang W, St-Pierre J, Lin J, Seale P, Spiegelman BM Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation. Cell Metab. 2006 May;3(5):333-41.
- Arany, Zoltan, MD, PhD
- Cooper, Marcus, MD
- Girnun, Geoffrey, PhD
- Handschin, Christophe, PhD
- Lin, Jiandie, PhD
- Mueller, Elisabetta, PhD
- Devarakonda, Srikripa, PhD
- Drori, Stavit, PhD
- Jaeger, Sybille, PhD
- Seale, Patrick, PhD
- Pierre, Julie St., PhD
- Uldry, Marc, PhD
- Walkey, Chris, PhD
- Yang, Wenli, PhD