Transgenerational inheritance of the insulin-resistant phenotype in embryo-transferred intrauterine growth-restricted adult female rat offspring.
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 pPKCzeta, and PKCzeta 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.
Thamotharan
Manikkavasagar
M
Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles.
Garg
Meena
M
Oak
Shilpa
S
Rogers
Lisa M
LM
Pan
Gerald
G
Sangiorgi
Frank
F
Lee
Paul W N
PW
Devaskar
Sherin U
SU
D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight / Q000502:physiology; D004624:Embryo Transfer; D044127:Epigenesis, Genetic; D005260:Female; D005317:Fetal Growth Retardation / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D009929:Organ Size / Q000502:physiology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D007328:Insulin; C495694:Slc2a4 protein, rat