Transcriptional Basis Of Energy Metabolism In Health And Disease
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.
- 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. Recently, we have begun to explore the transcriptional control of brown fat differentiation. Since brown fat cells dissipate energy as heat, this is an interesting potential avenue into the obesity/diabetes problem. IN 2007 and 2008, we identified PRDM16 as a “master” regulator of brown fat cell determination. Shortly thereafter, we identified a second type of thermogenic cell, the beige adipocyte. We are now studying their development, regulation and their ability to control whole body energy homeostasis.
- 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 and hepatic gluconeogenesis are both induced via expression of PGC-α, which then docks on a variety of transcription factor targets. The PGC1? gene is induced with exercise in muscle and the encoded protein plays very important roles in the adaptation of skeletal muscle to endurance exercise. We recently identified an isoform of PGC1a termed PGC1a4 that is increased with resistance training and stimulates muscle hypertrophy and resistance to atrophy. Current projects are centered on how the PGC-1 coactivators (and PRDM16) function mechanistically via recruiting chromatin modifying enzymes. This is a major collaboration with the HMS proteomics group of Steve Gygi. 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.3.
- Chemical Biology Of The PGC-1 Coactivators. Since the PGC-1's have many activities to modulate muscle wasting, neurodegeneration and energy balance in vivo, we have embarked on collaborations with the Broad Institute and Scripps Institute to find chemical compounds that can modulate PGC-1 amounts and activities. We have started with sets of known drugs where the pharmacology is known. However, we are also screening larger sets of drugs and do new pharmacology where it is necessary, again in collaboration with the Broad and Scripps Institutes.
1. 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. PMID:19641492 PMCID: PMC2754867
2. Gupta RK, Arany Z, Seale P, Mepani RJ, Ye L, Conroe HM, Roby YA, Kulaga H, Reed RR, Spiegelman BM. Transcriptional Control of Preadipocyte Determination by Zfp423. Nature 2010; 464(7288):619-623. PMID:20200519 PMCID: PMC2845731
3. 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 PPAR? by Cdk5. Nature 2010; 466:451-456. PMID:20651683 PMCID: PMC2987584
4. Seale P, Conroe HM, Estall JL, Kajimura S, Frontini A, Ishibashi J, Cohen P, Cinti S, Spiegelman BM. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue. J Clin Invest. 2011; 121(1):96-105. PMID:21123942 PMCID:PMC3007155
5. Lustig Y, Ruas JL, Estall JL, Lo JC, Devarakonda S, Laznik D, Choi JH, Ono H, Olsen JV and Spiegelman BM. Separation of the Gluconeogenic and Mitochondrial Functions of PGC-1α through S6 Kinase. Genes & Dev. 2011; Jun 15; 25(12):1232-44. PMID:21646374 PMCID:PMC3127426
6. 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, Vidovi? D, Shulman GI, Spiegelman BM and Griffin PR. Anti-Diabetic Actions of a Non-Agonist PPARγ Ligand Blocking Cdk5-Mediated Phosphorylation. Nature 2011; 477–481. PMID:21892191 PMCID: PMC3179551
7. Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbachm KA, Boström EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Højlund K, Gygi SP, Spiegelman BM. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012; 481(7382):463-8. PMID:22237023 PMCID:PMC3522098
8. Wu J, Boström P, Sparks LM, Ye L, Choi JH, Giang A, Khandekar M, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerbäck S, Schrauwen P and Spiegelman BM. Beige Adipocytes are a Distinct Type of Thermogenic Fat Cell in Mouse and Human. Cell 2012; 150(2):366-76 PMID:22796012 PMCID:PMC3402601
9. Ruas JL, White JP, Rao RR, Kleiner S, Brannan KT, Harrison BC, Greene NP, Wu J, Estall JL, Irving BA, Lanza IR, Rasbach KA, Okutsu M, Nair KS, Yan Z, Leinwand LA, Spiegelman BM. A novel PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy. Cell 2012; 151(6):1319-31. PMID:23217713 PMCID: PMC3520615
10. Spiegelman BM. Banting lecture 2012: regulation of adipogenesis: toward new therapeutics for metabolic disease. Diabetes 2013: 62(6):1774-82. PMID:23704518 PMCID: PMC3661621
11. Cohen P, Levy JD, Zhang Y, Frontini A, Kolodin DP, Svensson KJ, Lo JC, Zeng X, Ye L, Khandekar MJ, Wu J, Gunawardana SC, Banks AS, Camporez JP, Jurczak MJ, Kajimura S, Piston DW, Mathis D, Cinti S, Shulman GI, Seale P, Spiegelman BM. Ablation of PRDM16 and Beige Fat Causes Metabolic Dysfunction and a Subcutaneous to Visceral Adipose Switch. Cell 2014; 156(1-2):304-16. PMID:24439384 PMCID:PMC3922400