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This Article Full Text Full Text (PDF) All Versions of this Article: 292/5/E1270    most recent 00462.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Thamotharan, M. Articles by Devaskar, S. U. Search for Related Content PubMed PubMed Citation Articles by Thamotharan, M. Articles by Devaskar, S. U.

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

¹Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine at the University of California Los Angeles (UCLA), Los Angeles; and ²Harbor-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

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