Shingo Kajimura Ph.D.
Molecular Basis of Fat Cell Development and Energy Homeostasis
Obesity is a major risk factor for metabolic disorders such as type-2 diabetes and cardiovascular disease. Adipose tissues serve as central regulators of energy homeostasis in response to a variety of environmental and genetic factors, by systemic signaling via secretion of various adipokines, and by adaptive thermogenesis. The main focus of our lab is to uncover the molecular circuits that control fat cell development and function by employing a wide range of molecular biology, developmental biology and biochemical approaches.
All mammals including humans harbor two types of adipose tissue that serve distinct physiological functions: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT functions mainly in the storage of excess energy, while BAT specializes in dissipating energy in the form of heat through a process called non-shivering thermogenesis, and functions as a defense against hypothermia and obesity. Due to its remarkable oxidative capacity to dissipate excess chemical energy, decreased BAT mass is closely linked to the development of obesity and metabolic disorders. Since recent studies clearly demonstrated the existence of active BAT depots in adult humans, altering the amount and activity of BAT could provide a novel therapeutic intervention to counteract obesity and metabolic syndrome.
Over the last several years, we have been studying the transcriptional regulation of brown fat development. We have recently defined PRDM16 (PR-domain containing 16) and C/EBPβ as a critical transcriptional unit that determines the cellular fate of brown fat. Significantly, ectopic expression of the two factors is sufficient to reconstitute a fully functional brown fat program in naïve fibroblastic cells, from mouse and man, in vivo.
Our goal is to further decode the transcriptional and epigenetic regulatory networks that govern fate determination and maintenance of brown fat cells, and to investigate their roles in controlling whole body energy metabolism. We hope these studies have applications to the development of novel therapies for obesity, insulin resistance and metabolic diseases.
Ohno H, Shinoda K, Spiegelman BM, Kajimura S. PPARγ agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metabolism 2012, 15(3):395-404.
Kajimura S., Seale P., and Spiegelman B.M. Transcriptional control of brown fat development. Cell Metabolism 2010, 11(4):257-262.
Choi J.H., Banks A.S., Estall J.L., Kajimura S., Boström P., Laznik D., Ruas J.L., Chalmers M.J., Kamenecka T.M., Blüher M., Griffin P.R., Spiegelman B.M. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5. Nature 2010, 466(7305):451-456.
Kajimura S., Seale P., Kubota K., Lunsford E., Frangioni J.V., Gygi S.P., and Spiegelman B.M. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-β transcriptional complex. Nature 2009, 460(7259): 1154-1158.
Kajimura S., Seale P., Tomaru T., Erdjument-Bromage H., Cooper M.P., Ruas J.L., Chin S., Tempst P., Lazar M.A., and Spiegelman B.M. Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex. Genes & Development 2008, 22(10): 1397-1409.
Seale P., Bjork, B., Yang, W., Kajimura, S., Kuang, S., Scime, A., Devarakonda, S., Chin, S., Conroe, H., Rudnicki, M.A., Beier, D.R., and Spiegelman, B.M. PRDM16 controls a brown fat/skeletal muscle developmental switch. Nature 2008, 454(7207): 961-967.
Seale P*., Kajimura S*., Yang W., Chin S., Rohas L.M., Uldry M., Tavernier G., Langin D., and Spiegelman B.M. Transcriptional control of brown fat determination by PRDM16. Cell Metabolism 2007, 6(1): 38-54. (* co-first author)