Article Text

PDF
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.
  1. Y. Vo,
  2. J. W. Leitner,
  3. L. Barbour,
  4. J. Friedman,
  5. B. Draznin
  1. VA Medical Center and University of Colorado Health Sciences Center, Denver, CO

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.

Statistics from Altmetric.com

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.