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© The Rockefeller University Press, 0021-9525/2000//667 $5.00
The Journal of Cell Biology, Volume 149, Number 3, , 2000 667-682

Roles of Autocrine TGF-β Receptor and Smad Signaling in Adipocyte Differentiation

^a Department of Growth and Development, Programs in Cell Biology and Developmental Biology, University of California at San Francisco, San Francisco, California 94143-0640
^b Department of Anatomy, Programs in Cell Biology and Developmental Biology, University of California at San Francisco, San Francisco, California 94143-0640
Department of Growth and Development, University of California at San Francisco, San Francisco, CA 94143-0640.(415) 476-1499(415) 476-7322

derynck{at}itsa.ucsf.edu

TGF-β inhibits adipocyte differentiation, yet is expressed by adipocytes. The function of TGF-β in adipogenesis, and its mechanism of action, is unknown. To address the role of TGF-β signaling in adipocyte differentiation, we characterized the expression of the TGF-β receptors, and the Smads which transmit or inhibit TGF-β signals, during adipogenesis in 3T3-F442A cells. We found that the cell-surface availability of TGF-β receptors strongly decreased as adipogenesis proceeds. Whereas mRNA levels for Smads 2, 3, and 4 were unchanged during differentiation, mRNA levels for Smads 6 and 7, which are known to inhibit TGF-β responses, decreased severely. Dominant negative interference with TGF-β receptor signaling, by stably expressing a truncated type II TGF-β receptor, enhanced differentiation and decreased growth. Stable overexpression of Smad2 or Smad3 inhibited differentiation and dominant negative inhibition of Smad3 function, but not Smad2 function, enhanced adipogenesis. Increased Smad6 and Smad7 levels blocked differentiation and enhanced TGF-β–induced responses. The inhibitory effect of Smad7 on adipocyte differentiation and its cooperation with TGF-β was associated with the C-domain of Smad7. Our results indicate that endogenous TGF-β signaling regulates the rate of adipogenesis, and that Smad2 and Smad3 have distinct functions in this endogenous control of differentiation. Smad6 and Smad7 act as negative regulators of adipogenesis and, even though known to inhibit TGF-β responses, enhance the effects of TGF-β on these cells.

Key Words: inhibitory Smads • PPAR • C/EBP • 3T3-F442A • retroviral vectors

© 2000 The Rockefeller University Press

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