Transgenerational inheritance of the insulin-resistant phenotype in embryo-transferred intrauterine growth-restricted adult female rat offspring

• Published in: American journal of physiology: endocrinology and metabolism 2007-05, Vol.292 (5), p.E1270-E1279
• Main Authors: Thamotharan, Manikkavasagar, Garg, Meena, Oak, Shilpa, Rogers, Lisa M, Pan, Gerald, Sangiorgi, Frank, Lee, Paul W. N, Devaskar, Sherin U
• Format: Article
• Language: English
• Subjects: Animals; Area Under Curve; Blood Glucose - metabolism; Body Weight - physiology; Embryo Transfer; Endocrinology; Epigenesis, Genetic; Female; Fetal Growth Retardation - blood; Fetal Growth Retardation - genetics; Fetal Growth Retardation - metabolism; Genetics; Genotype & phenotype; Glucose Tolerance Test; Glucose Transporter Type 4 - metabolism; Insulin; Insulin - blood; Insulin - metabolism; Insulin - pharmacology; Insulin Resistance - genetics; Liver - metabolism; Male; Metabolism; Muscle, Skeletal - metabolism; Organ Size - physiology; Pregnancy; Rats; Rats, Sprague-Dawley; Rodents
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00462.2006

1 Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine at the University of California Los Angeles (UCLA), Los Angeles; and 2 Harbor-UCLA Medical Center, Torrance, California Submitted 1 September 2006 ; accepted in final form 12 December 2006 To determine mechanisms underlying the transgenerational presence of metabolic perturbations in the intrauterine growth-restricted second-generation adult females (F2 IUGR) despite normalizing the in utero metabolic environment, we examined in vivo glucose kinetics and in vitro skeletal muscle postinsulin receptor signaling after embryo transfer of first generation (F1 IUGR) to control maternal environment. Female F2 rats, procreated by F1 pre- and postnatally nutrient- and growth-restricted (IUGR) mothers but embryo transferred to gestate in control mothers, were compared with similarly gestating age- and sex-matched control (CON) F2 progeny. Although there were no differences in birth weight or postnatal growth patterns, the F2 IUGR had increased hepatic weight, fasting hyperglycemia, hyperinsulinemia, and unsuppressed hepatic glucose production, with no change in glucose futile cycling or clearance, compared with F2 CON. These hormonal and metabolic aberrations were associated with increased skeletal muscle total GLUT4 and pAkt concentrations but decreased plasma membrane-associated GLUT4, total pPKC , and PKC enzyme activity, with no change in total SHP2 and PTP1B concentrations in IUGR F2 compared with F2 CON. We conclude that transgenerational presence of aberrant glucose/insulin metabolism and skeletal muscle insulin signaling of the adult F2 IUGR female offspring is independent of the immediate intrauterine environment, supporting nutritionally induced heritable mechanisms contributing to the epidemic of type 2 diabetes mellitus. glucose transporter; metabolic imprinting; epigenetic inheritance Address for reprint requests and other correspondence: S. U. Devaskar, Dept. of Pediatrics, 10833, Le Conte Ave., MDCC-B2-375, Los Angeles, CA 90095-1752 (e-mail address: sdevaskar{at}mednet.ucla.edu )