BADERC-Bruce M. Spiegelman

Bruce M. Spiegelman, Ph.D.

Transcriptional Regulation of Energy Metabolism

Transcription Basis of Adipogenesis: A Major area of our lab is focused on the mechanisms of fat cell differentiation. In 1994 we identified an orphan nuclear receptor, PPARg, as a master switch for the differentiation of adipocytes (Tontonoz et al., 1994). We and other labs later illustrated that PPARg functions in a network with proteins of the C/EBP family (Wu et al., 1999; Rosen et al., 2002). Genetic studies have conclusively illustrated that PPARg is both sufficient and necessary for fat tissue development (Rosen et al., 1999).

Current studies are centered around the structure and function of the PPARg complex. This includes identification of coactivator proteins that dock on PPARg when it is activated by synthetic or natural ligands. In addition, identification of the natural ligand of PPARg that activates adipogenesis is a key future goal.

Regulation of Oxidative Metabolism and Gluconeogenesis Via the Coactivator PGC-1a: Our studies of brown fat differentiation led to the discovery of a coactivator of PPARg, PGC-1 (now PGC-1a) that can turn on broad aspects of oxidative metabolism (Puigserver et al., 1998). PGC-1a activates mitochondrial biogenesis in many cell types (Wu et al., 1999), and induces muscle fiber-type switching toward more Type 1 fibers (Lin et al., 2002). Since type 1 muscle fibers are more insulin sensitive, the ability to manipulate these pathways may have therapeutic implications in diabetes. In addition, PGC-1a activates many aspects of the fasting response in liver, including the activation of gluconeogenesis and b-oxidation of fatty acids (Yoon et al., 2001; Rhee et al., 2003).

A key future area is the genetic manipulation of PGC-1a, and its close homology, PGC-1b in mice via loss of function studies. These may include general knock-outs, tissue specific knock-outs, and knock-ins.

References:

1. Tontonoz P, Hu E and Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPARg2, a lipid-activated transcription factor. Cell 1994; 79:1147-1156.

2. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla R and Spiegelman BM. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 1999; 98:115-124.

3. Rosen ED, HsuC-H, Wang X, Sakai S, Freeman MW, Gonzalez FJ and Spiegelman BM. C/EBPa induces adipogenesis through PPARg: An unified pathway. Genes & Dev. 2002; 16: 22-26.

4. Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone D, Spiegelman BM and Mortensen R. PPARg is required for adipogenesis in vivo and in vitro. Molecular Cell 1999; 4:611-617.

5. Lin, J, Tarr, P, Puigserver P, Olson, E, Lowell BB, Zhang CY, Boss O, Bassel-Duby R and Spiegelman, BM. Transcritional Coactivator PGC-1alpha drives the expression of Slow-Twitch Muscle Fibres. Nature 2002; 418:797-801.

6. Yoon JC, Puigserver P, Chen G, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB and Spiegelman BM. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 2001; 413:131-138.

7. Rhee J, Inoue Y, Yoon JC, Puigserver P, Fan M, Gonzalez FJ and Spiegelman BM. Regulation of the hepatic fasting response by PPARgamma Coactivator-1alpha (PGC-1): Requirement for HNF4a in gluconeogenesis. Proc Natl Acad Sci USA 2003; 100:4012-4017.

8. 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-1alpha interaction. Nature. 2003;423:550-5.

9. Yoon JC, Xu G, Deeney JT, Yang SN, Rhee J, Puigserver P, Levens AR, Yang R, Zhang CY, Lowell BB, Berggren PO, Newgard CB, Bonner-Weir S, Weir G, Spiegelman BM. Suppression of beta cell energy metabolism and insulin release by PGC-1alpha. Dev Cell. 2003;5:73-83.

10. Fan M, Rhee J, St-Pierre J, Handschin C, Puigserver P, Lin J, Jaeger S, Erdjument-Bromage H, Tempst P, Spiegelman BM. Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1alpha: modulation by p38 MAPK. Genes Dev. 2004;18:278-89.

11. 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-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proc Natl Acad Sci U S A. 2004;101:6570-5.






			Bruce M. Spiegelman, Ph.D. Transcriptional Regulation of Energy Metabolism Transcription Basis of Adipogenesis: A Major area of our lab is focused on the mechanisms of fat cell differentiation. In 1994 we identified an orphan nuclear receptor, PPARg, as a master switch for the differentiation of adipocytes (Tontonoz et al., 1994). We and other labs later illustrated that PPARg functions in a network with proteins of the C/EBP family (Wu et al., 1999; Rosen et al., 2002). Genetic studies have conclusively illustrated that PPARg is both sufficient and necessary for fat tissue development (Rosen et al., 1999). Current studies are centered around the structure and function of the PPARg complex. This includes identification of coactivator proteins that dock on PPARg when it is activated by synthetic or natural ligands. In addition, identification of the natural ligand of PPARg that activates adipogenesis is a key future goal. Regulation of Oxidative Metabolism and Gluconeogenesis Via the Coactivator PGC-1a: Our studies of brown fat differentiation led to the discovery of a coactivator of PPARg, PGC-1 (now PGC-1a) that can turn on broad aspects of oxidative metabolism (Puigserver et al., 1998). PGC-1a activates mitochondrial biogenesis in many cell types (Wu et al., 1999), and induces muscle fiber-type switching toward more Type 1 fibers (Lin et al., 2002). Since type 1 muscle fibers are more insulin sensitive, the ability to manipulate these pathways may have therapeutic implications in diabetes. In addition, PGC-1a activates many aspects of the fasting response in liver, including the activation of gluconeogenesis and b-oxidation of fatty acids (Yoon et al., 2001; Rhee et al., 2003). A key future area is the genetic manipulation of PGC-1a, and its close homology, PGC-1b in mice via loss of function studies. These may include general knock-outs, tissue specific knock-outs, and knock-ins. References: 1. Tontonoz P, Hu E and Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPARg2, a lipid-activated transcription factor. Cell 1994; 79:1147-1156. 2. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla R and Spiegelman BM. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 1999; 98:115-124. 3. Rosen ED, HsuC-H, Wang X, Sakai S, Freeman MW, Gonzalez FJ and Spiegelman BM. C/EBPa induces adipogenesis through PPARg: An unified pathway. Genes & Dev. 2002; 16: 22-26. 4. Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone D, Spiegelman BM and Mortensen R. PPARg is required for adipogenesis in vivo and in vitro. Molecular Cell 1999; 4:611-617. 5. Lin, J, Tarr, P, Puigserver P, Olson, E, Lowell BB, Zhang CY, Boss O, Bassel-Duby R and Spiegelman, BM. Transcritional Coactivator PGC-1alpha drives the expression of Slow-Twitch Muscle Fibres. Nature 2002; 418:797-801. 6. Yoon JC, Puigserver P, Chen G, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB and Spiegelman BM. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 2001; 413:131-138. 7. Rhee J, Inoue Y, Yoon JC, Puigserver P, Fan M, Gonzalez FJ and Spiegelman BM. Regulation of the hepatic fasting response by PPARgamma Coactivator-1alpha (PGC-1): Requirement for HNF4a in gluconeogenesis. Proc Natl Acad Sci USA 2003; 100:4012-4017. 8. 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-1alpha interaction. Nature. 2003;423:550-5. 9. Yoon JC, Xu G, Deeney JT, Yang SN, Rhee J, Puigserver P, Levens AR, Yang R, Zhang CY, Lowell BB, Berggren PO, Newgard CB, Bonner-Weir S, Weir G, Spiegelman BM. Suppression of beta cell energy metabolism and insulin release by PGC-1alpha. Dev Cell. 2003;5:73-83. 10. Fan M, Rhee J, St-Pierre J, Handschin C, Puigserver P, Lin J, Jaeger S, Erdjument-Bromage H, Tempst P, Spiegelman BM. Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1alpha: modulation by p38 MAPK. Genes Dev. 2004;18:278-89. 11. 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-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proc Natl Acad Sci U S A. 2004;101:6570-5.