US EPA

7159398 

Journal Article 

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

Ribon, V; Johnson, JH; Camp, HS; Saltiel, AR; , 

1998 

Proceedings of the National Academy of Sciences of the United States of America 

NATL ACAD SCIENCES 

WASHINGTON 

14751-14756 

9843961 

WOS:000077436700031 

c-Cbl-associated protein (CAP) is a signaling protein that interacts with both c-Cbl and the insulin receptor that may be involved in the specific insulin-stimulated tyrosine phosphorylation of c-Cbl. The restricted expression of CAP in cells metabolically sensitive to insulin suggests an important potential role in insulin action. The expression of CAP mRNA and proteins are increased in 3T3-L1 adipocytes by the insulin sensitizing thiazolidinedione drugs, which are activators of the peroxisome proliferator-activated receptor 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 tyrosine phosphorylation. Administration of the thiazolidinedione troglitazone to Zucker (fa/fa) rats markedly increased the expression of the major CAP isoform in adipose tissue. This effect was sustained for up to 12 weeks of treatment 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.