149 EFFECT OF GROWTH HORMONE ON EXPRESSION OF P85α AND PHOSPHATIDYLINOSITOL 3-KINASE ACTIVITY IN 3T3-L1 CELLS AND EPIDIDYMAL FAT OF WILD-TYPE AND P85α+/- MICE. (1st January 2006)

• Record Type: Journal Article
• Authors: Vo, Y.; Leitner, J. W.; Barbour, L.; Friedman, J.; Draznin, B.
• Is Part Of: Journal of investigative medicine. Volume 54:Number 1(2006)
• Page Start: S105
• Page End: S105
• Publication Date: 2006-01-01
• Subjects: Clinical medicine -- Periodicals; Medicine -- Research -- Periodicals; Medicine; Research -- United States; Clinical medicine; Medicine -- Research; Periodicals; 616.075
• DOI: 10.2310/6650.2005.X0004.148
• Languages: English
• ISSNs: 1081-5589

Abstract

Abstract : Phosphatidylinositol 3-kinase (PI 3-k) plays a critical role in mediating metabolic signaling of insulin. PI 3-k consists of a regulatory p85 (with p85α being the major isoform) and a catalytic p110 subunits. The regulatory subunit p85 exists in excess to p110, creating a certain balance between the free p85 monomer and a p85-p110 heterodimer complex that possesses PI 3-k activity. Because p85 monomer competes with the heterodimer for the IRS-1 binding sites, increases in p85 expression displace p85-p110 heterodimer from IRS-1, resulting in a decreased PI 3-k activity. This can occur in type 2 diabetes, obesity, and pregnancy, when insulin resistance is induced by human placental growth hormone (GH). In this study we tested the direct effect of GH on p85a expression in 3T3-L1 cells and in fat cells obtained from wild-type (WT) mice and mice with heterozygous deletion of p85α +/- . Results: Incubation of 3T3-L1 pre-adipocytes with increasing concentrations of rat recombinant GH (0, 500, and 2, 500 ng/mL) for 24 hr increased p85α protein expression by approximately 250% ( p < .001). In contrast, expression of p110 was not affected. In vivo insulin injection (10 U/kg BW) activated PI 3-k in the epididymal fat of WT and p85α+/- mice (p < .01). Administration of GH for 3 days (1 mg/kg s/c twice daily) blocked insulin-stimulated IRS-1-associated PI 3-k activity in the WT but not in p85α+/- mice. Conclusions: GH induces insulin resistance by increasing expression of p85α and creating an imbalance between the subunits of PI 3-k. Increases in p85α compete with p85-p110 heterodimer at the IRS-1 binding sites, resulting in decreased PI 3-k activity.