Thiazolidinediones and insulin resistance: Peroxisome proliferator-activated receptor gamma activation stimulates expression of the CAP gene

c-Cbl-associated protein (CAP) is a signaling protein that interacts with b oth c-Cbl and the insulin receptor that may be involved in the specific ins ulin-stimulated tyrosine phosphorylation of c-Cbl. The restricted expressio n of CAP in cells metabolically sensitive to insulin suggests an important potential role in insulin action. The expression of CAP mRNA and proteins a re increased in 3T3-L1 adipocytes by the insulin sensitizing thiazolidinedi one drugs, which are activators of the peroxisome proliferator-activated re ceptor gamma (PPAR gamma). The stimulation of CAP expression by PPAR gamma activators results from increased transcription. This increased expression of CAP was accompanied by a potentiation of insulin-stimulated c-Cbl tyrosi ne phosphorylation. Administration of the thiazolidinedione troglitazone to Zucker (fa/fa) rats markedly increased the expression of the major CAP iso form in adipose tissue. This effect was sustained for up to 12 weeks of tre atment and accompanied the ability of troglitazone to prevent the onset of diabetes and its complications. Thus, CAP is the first PPAR gamma-sensitive gene identified that participates in insulin signaling and may play a role in thiazolidinedione-induced insulin sensitization.