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Current Research:
The long term goal of my research program is to determine the molecular mechanisms by which extracellular signals regulate adipocyte differentiation and metabolism. We have pioneered investigations into the role of Wnt signaling as a potent, endogenously produced inhibitor of adipogenesis. Wnt10b acts as an adipogenic switch, which must be shut off for cultured preadipocyte models to differentiate in vitro. Work from my laboratory has revealed that Wnt signaling, likely initiated by Wnt-10b, maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors, C/EBPa and PPARg. Ectopic expression of Wnt or activation of intermediates of the canonical Wnt signaling pathway results in potent inhibition of adipogenesis in cultured preadipocytes. Moreover, blocking Wnt signaling in preadipocytes by genetic means or by inhibiting Wnt action extracellularly triggers spontaneous conversion into adipocytes, indicating that endogenous Wnt signaling acts to repress the differentiation process. We are currently exploring the importance of Wnt10b in regulation of white adipose tissue development in vivo. Understanding the role of Wnt signaling in the development of adipose tissues will provide important insight into the medical problems of obesity and type II diabetes, two major health risks in the United States.
Representative
Publications:
Ross, S.E., N. Hemati, K.A. Longo, C. N. Bennet, P. Lucas, and R.L.
Erickson, O.A. MacDougald. 2000. Inhibition of Adipogenesis by Wnt
Signaling. Science 289: 950-953.
Kennell, J.A., E.E. O’Leary, B.M. Gummow, Gary D. Hammer, and O.A.
MacDougald. 2003. 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.
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. 2004.
Phosphorylation of C/EBPa inhibits granulopoiesis. Molecular and
Cellular Biology 24:675-686.
Longo, K.A., W.S. Wright, S. Kang, I. Gerin, S.-H. Chiang, P.C. Lucas,
M.R. Opp, and O.A. MacDougald. 2004. Wnt10b Inhibits Development of
White and Brown Adipose Tissues. Journal of Biological Chemistry. 279:
35503-35509.
Kang, S., L. Bajnok, K.A. Longo, R.K. Petersen, J.B. Hansen, K. Kristiansen, O.A. MacDougald. 2005. Effects of Wnt signaling on brown adipocyte differentiation and metabolism mediated by PGC-1. Molecular and Cellular Biology. 25: 1272-1282.
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. 2005. LXRb is required for adipocyte growth, glucose homeostasis and b cell function in aged mice. Journal of Biological Chemistry 280: 23024-23031.
Bennett, C.N., K.A. Longo, W.S. Wright, L.J. Suva, T.F. Lane, K.D. Hankenson and O.A. MacDougald. 2005. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proceedings of the National Academy of Sciences. 102: 3324-3329.
Kennell, J.A. and O.A. MacDougald. 2005. Inhibition of adipogenesis by b-catenin-dependent and independent Wnt signaling. Journal of Biological Chemistry. 280: 24004-24010.
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