INHIBITION OF ADIPOGENESIS BY THE STRESS-INDUCED PROTEIN CHOP (GADD153)

Adipocytic conversion of 3T3-L1 cells is dependent on induction of tra nscription factors from the C/EBP family that activate promoters of ad ipogenic genes, We find that expression of CHOP, a nuclear protein tha t dimerizes avidly with C/EBP isoforms alpha and beta and directs the resulting heterodimer away from classic C/EBP-binding sites, markedly inhibits this differentiation process, Surprisingly, the presence of C HOP early in the differentiation process inhibits C/EBP alpha and beta gene expression. Ectopic expression of C/EBP alpha bypasses the inhib itory effect of CHOP on differentiation, providing further evidence th at CHOP action is mediated by inhibition of C/EBP alpha gene expressio n rather than merely inhibiting the encoded protein's DNA-binding acti vity. A similar pattern of attenuated expression of C/EBP alpha and be ta is also observed in cells induced to differentiate in media with lo w glucose concentration. This stressed culture condition is associated with induction of endogenous CHOP and marked attenuation of the diffe rentiation process. Our data suggest that CHOP functions as an inducib le inhibitor of adipocytic differentiation in response to metabolic st ress. It does so by interfering with the accumulation of adipogenic C/ EBP isoforms.