TRANSCRIPTION Dueling Transcription Factors in Adipogenesis

The nuclear hormone receptor family member PPAR (peroxisome proliferator-activated receptor ) has important insulinomimetic functions in lipid homeostasis. Dowell et al. used a yeast two-hybrid screen to detect interacting proteins and identified Foxo1, a transcription factor that regulates multiple biological processes including insulin action and metabolic control. Foxo proteins are phosphorylated in response to insulin, which results in decreased transcriptional activity, and constitutively active Foxo1 is antiadipogenic. PPAR, on the other hand, has insulin-like proadipogenic actions. Transcriptional reporter assays in human embryonic kidney 293T cells showed that PPAR and Foxo1 each had inhibitory effects on transcription mediated by the other factor. In C. elegans, genetic interactions occur between genes encoding an insulin receptor-like gene, daf-2; a Foxo-like gene, daf-16; and a nuclear hormone receptor, daf-12. In vitro, DAF-16 and DAF-12 interacted, as did their mammalian counterparts. DAF-12 also interacted, although more weakly, with mammalian Foxo proteins. The authors propose that there may be an evolutionarily conserved mechanism by which insulin and PPAR antagonize actions of Foxo proteins and vice versa. Further elucidation of such mechanisms would enhance our understanding of adipogenesis and insulin sensitivity.

P. Dowell, T. C. Otto, S. Adi, M. D. Lane, Convergence of peroxisome proliferator-activated receptor and Foxo1 signaling pathways. J. Biol. Chem. 278, 45485-45491 (2003). [Abstract] [Full Text]