Current Research:
One of the goals of my research program is to determine the molecular mechanisms by which extracellular signals regulate mesenchymal cell fate decisions. Mesenchymal stem cells have the capacity to differentiate into a number of cell types, including adipocytes, osteoblasts and myocytes. While the focus of my lab has been on defining the genetic program of adipogenesis and its regulation by Wnt signaling, we are now extending this line of research to signals that determine whether stem cells differentiate into adipocytes or osteoblasts. Understanding the switch between these two cell types is relevant to human physiology because in a variety of clinical conditions, decreases in bone mass are typically accompanied by increases in marrow adipocytes. We have pioneered investigations into the role of Wnt10b as an inhibitor of adipogenesis in cultured preadipocytes and in transgenic mice. In addition to having less adipose tissue, mice that express Wnt10b in adipocytes and bone marrow have a four-fold increase in trabecular bone. This appears to be a direct effect of Wnt10b on fate of mesenchymal precursors because activation of Wnt signaling in pluripotent cell lines increases osteoblastogenesis and decreases adipogenesis. Evidence that it is Wnt10b that specifically plays a role in fate of mesenchymal stem cells comes from our observation that Wnt10b -/- mice have ~30% less trabecular bone. Although not as fully developed, there is considerable in vitro evidence that Wnt signaling also controls cell fate decisions between adipocytes and myocytes. As Wnt10b expression declines in mice as they age, this signaling molecule may be integral to the increase in adiposity and decrease in bone and muscle that occurs after midlife. Understanding the role of Wnt signaling in the development of adipose tissues, bone, and muscle will provide important insight into the medical problems of obesity, type II diabetes, and osteoporosis, all major health risks in the United States.
Representative Publications:
Wright, W.S., K.A. Longo, V.W. Dolinsky, I. Gerin, S. Kang, C.N. Bennett, S.-H. Chiang, T.C. Prestwich, C. Gress, C.F. Burant, V.S. Susulic, and O.A. MacDougald. 2007. Wnt10b inhibits obesity in ob/ob and agouti mice. Diabetes 56: 295-303.
Kang, S., C.N. Bennett, L.A. Rapp, K.D. Hankenson, and O.A. MacDougald. 2007. Wnt signaling stimulates osteoblastogenesis of mesenchymal precursors by suppressing C/EBPα and PPARγ. Journal of Biological Chemistry 282: 14515-24.
Bennett, C.N., H. Ouyang, Y. Ma, I. Gerin, K. Sousa, Q. Zeng, T.F. Lane, V. Krishnan, K.D. Hankenson, and O.A. MacDougald. 2007. Expression of Wnt10b increases postnatal bone formation by enhancing osteoblast differentiation. Journal of Bone and Mineral Research 22: 1924-1932.
Cha, H.C., N.R. Oak, S. Kang, T.-A. Tran, S. Kobayashi, S.-H. Chiang, D.G. Tenen, and O.A. MacDougald. 2008. Phosphorylation of C/EBPα regulates GLUT4 expression and glucose transport in adipocytes. Journal of Biological Chemistry (in press).
Keller, P., J. Petrie, P. de Rose, I. Gerin, W.S. Wright, A. Rinnov, C.P. Fischer, B.K. Pedersen, and O.A. MacDougald. 2008. Fat specific protein 27 regulates storage of triacylglycerol. Journal of Biological Chemistry (in press).
Ross, S.E., N. Hemati, K.A. Longo, C. N. Bennet, P. Lucas, and R.L. Erickson, O.A. MacDougald. "Inhibition of Adipogenesis by Wnt Signaling." Science, 289: 950-953 2000.
Kennell, J.A., E.E. O’Leary, B.M. Gummow, Gary D. Hammer, and O.A. MacDougald. "TCF-4N, A Novel Isoform of Mouse TCF-4, Synergizes with Beta-Catenin to Coactivate C/EBPa and SF-1 Transcription Factors." Molecular and Cellular Biology, 23: 5366-5375 2003.
Ross, S.E., H.S. Radomska, F. Schaufele, P. Zhang, J.N. Winnay, L. Bajnok, W.S. Wright, D.G. Tenen and O.A. MacDougald. "Phosphorylation of C/EBPa Inhibits Granulopoiesis." Molecular and Cellular Biology, 24:675-686 2004.
Longo, K.A., W.S. Wright, S. Kang, I. Gerin, S.-H. Chiang, P.C. Lucas, M.R. Opp, and O.A. MacDougald. "Wnt10b Inhibits Development of White and Brown Adipose Tissues." Journal of Biological Chemistry, 279: 35503-35509 2004.
Kang, S., L. Bajnok, K.A. Longo, R.K. Petersen, J.B. Hansen, K. Kristiansen, O.A. MacDougald. "Effects of Wnt Signaling on Brown Adipocyte Differentiation and Metabolism Mediated by PGC-1." Molecular and Cellular Biolog, 25: 1272-1282 2005.
Gerin, I., V.W. Dolinsky, J.G. Shackman, R.T. Kennedy, S.-H. Chiang, C.F. Burant, K. Steffensen, J-Ä.Gustafsson, and O.A. MacDougald. "LXRb is Required for Adipocyte Growth, Glucose Homeostasis and B Cell Function in Aged Mice." Journal of Biological Chemistry, 280: 23024-23031 2005.
Bennett, C.N., K.A. Longo, W.S. Wright, L.J. Suva, T.F. Lane, K.D. Hankenson and O.A. MacDougald. "Regulation of Osteoblastogenesis and Bone Mass by Wnt10b." Proceedings of the National Academy of Sciences, 102: 3324-3329 2005.
Kennell, J.A. and O.A. MacDougald. "Inhibition of Adipogenesis by B-Catenin-Dependent and Independent Wnt Signaling." Journal of Biological Chemistry, 280: 24004-24010 2005.
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