title: Peroxisome proliferator-activated receptor-gamma agonist improves skeletal muscle insulin signaling in the pregestational intrauterine growth-restricted rat offspring.
abstract: The effect of early intervention with a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist on skeletal muscle GLUT4 translocation and insulin signaling was examined in intrauterine (IUGR) and postnatal (PNGR) growth-restricted pregestational female rat offspring. Rosiglitazone [11 mumol/day provided from postnatal day (PN)21 to PN60] improved skeletal muscle insulin sensitivity and GLUT4 translocation in prenatal nutrient restriction [50% calories from embryonic day (e)11 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 libitum 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 in Con (P < 0.005). While no change in p85-phosphatidylinositol 3-kinase (PI3-K) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was observed, a decrease in protein tyrosine phosphatase 1B (PTP1B; P < 0.0002) and SH2-containing protein tyrosine phosphatase 2 (SHP2; P < 0.05) contributing to the rosiglitazone-induced insulin sensitivity was seen only in IUGR+PNGR. In contrast, an increase in phosphorylated 5'-adenosine monophosphate kinase (pAMPK; P < 0.04) and insulin responsiveness of phosphorylated phosphoinositide-dependent protein kinase-1 (pPDK1; P < 0.05), pAkt (P < 0.01), and particularly pPKCzeta (P < 0.0001) and its corresponding enzyme activity (P < 0.005) were observed in all four experimental groups. We conclude that early introduction of PPARgamma 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 intrauterine and postnatal growth-restricted offspring.
authors.affiliation: Department of Pediatrics, Division of Neonatology, Neonatal Research Center, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Oak
authors.forename: Cang
authors.initials: C
authors.lastname: Tran
authors.forename: Maria-Olivia
authors.initials: MO
authors.lastname: Castillo
authors.forename: Shanthie
authors.initials: S
authors.lastname: Thamotharan
authors.forename: Manikkavasagar
authors.initials: M
authors.lastname: Thamotharan
authors.forename: Sherin U
authors.initials: SU
authors.lastname: Devaskar
mesh_terms: D000465:Algorithms; D000818:Animals; D004353:Drug Evaluation, Preclinical; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000534:rehabilitation; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006128:Growth / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism* / Q000503:physiopathology / Q000534:rehabilitation; D051381:Rats; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; D047495:PPAR gamma; C495694:Slc2a4 protein, rat; D045162:Thiazolidinediones; D000077154:Rosiglitazone