Submitted on January 6, 2009
Revised on April 30, 2009
Accepted on May 28, 2009
Peroxisome Proliferator-Activated Receptor
Agonist Improves Skeletal Muscle Insulin Signaling in Pre-gestational Intrauterine Growth Restricted Rat Offspring
Shilpa Oak1, Cang Tran1, Maria-Olivia Castillo1, Shanthie Thamotharan2, Manikkavasagar Thamotharan1, and Sherin U. Devaskar1*
1 David Geffen School of Medicine UCLA
2 University of California at Los Angeles
* To whom correspondence should be addressed. E-mail: sdevaskar{at}mednet.ucla.edu.
The effect of early intervention with a PPAR
agonist on skeletal muscle GLUT4 translocation and insulin signaling was examined in the intrauterine and postnatal growth restricted pre-gestational female rat offspring. Rosiglitazone (11 µmol/day was provided from PN21 to PN60) improved skeletal muscle insulin sensitivity and GLUT4 translocation in prenatal nutrient restriction (50% calories from e11 to e21; IUGR) with (IUGR+PNGR) and without (IUGR) postnatal nutrient restriction (50% calories from PN1 to PN21; PNGR) similar to that of control (ad lib feeds throughout; CON) (n=6 each). This was accomplished by diminished basal and improved insulin responsive GLUT4 association with the plasma membrane in IUGR, IUGR+PNGR and PNGR mimicking that of CON (p<0.005). While no change in p85-PI-3-K and PTEN was observed, a decrease in PTP1B (p<0.0002) and SHP2 (p<0.05) contributing to the rosiglitazone induced insulin sensitivity was seen only in IUGR+PNGR. In contrast, an increase in pAMPK (p<0.04) and insulin responsiveness of pPDK1 (p<0.05), pAkt (p<0.01) and particularly pPKC
(p<0.0001) and its corresponding enzyme activity (p<0.005) were observed in all four experimental groups. We conclude that early introduction of PPAR agonist improved skeletal muscle activation of AMPK and insulin signaling resulting in insulin-independent AMPK and insulin responsive GLUT4 association with plasma membranes in IUGR, IUGR+PNGR and PNGR adult offspring, similar to that of CON. These findings support a role for insulin sensitizers in preventing the subsequent development of gestational or type 2 diabetes mellitus in the intrauterine and postnatal growth restricted offspring.
