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

Abstract

To determine mechanisms underlying the transgenerational presence of metabolic perturbations in the intrauterine growth-restricted secondgeneration 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 nutrientand 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 EPIDEMIOLOGICAL INVESTIGATIONS have linked pre-and postnatal nutrient restriction to adult-onset insulin resistance/type 2 diabetes mellitus, obesity, hypertension, and coronary artery disease (1, 2). Mimicking these conditions, animal models exposing the fetus or newborn to malnutrition in the form of either global (8,24,32) or selective nutrient restriction (6) with concomitant growth restriction predispose the adult offspring toward developing glucose intolerance (8, 24) and insulin resistance of postreceptor insulin-signaling pathways in skeletal muscle (21) and adipose tissue (6). This phenotype of aberrant glucose/insulin homeostasis persists transgenerationally from a gestationally diabetic adult intrauterine growthrestricted (IUGR) mother to the offspring (4). Various investigations have demonstrated a role for diminished pancreatic ␤-cells in type 2 diabetes mellitus as well, an aberration that is passed on transgenerationally (3, 17, 27). Although mutations of genetic loci responsible for insulin production are inherited (33, 34), emerging information suggests epigenetic regulation underlying this transgenerational inheritance pattern (7, 13, 18).In the first-generation (F1) adult female IUGR offspring with pre-and postnatal nutrient restriction, metabolic adaptations concerning glucose/insulin homeostasis consist of a diminution in glucose-induced insulin response with emerging hepatic insulin resistance (8) ...

Maternal obesity and fetal programming: effects of a high-carbohydrate nutritional modification in the immediate postnatal life of female rats

“…In contrast, studies by Gill-Randall et al (18) have shown that embryos from the diabetic Goto-Kakizaki rat developing in the normoglycemic Wistar intrauterine environment developed diabetes, showing that genetic predisposition to diabetes is not alleviated by a euglycemic intrauterine environment. In another study, embryos from intrauterine growth-retarded F1 generation females, when transferred to a normal intrauterine environment, still developed the maternal phenotype, indicating the dominant effect of epigenetic modifications (36). Future studies should determine whether in the third generation of HC rats genetic propensity (established probably due to epigenetic alterations) would gain dominance over the intrauterine environment by transferring embryos from 2-HC rats to MF females.…”

Essential nutrient supplementation prevents heritable metabolic disease in multigenerational intrauterine growth‐restricted rats

“…Recently, a study focusing on the F2 generation uncovered that rats with low maternal birth weight due to late-gestation (e19) uteroplacental insufficiency exhibited a sex-specific reduced insulin response and altered pancreatic morphology (55). In another study, female F2 rats exhibited increased hepatic weight with aberrant glucose and insulin metabolism (74). Natural experiments and comparisons to human populations have borne out the validity of the rodent IUGR models, finding similarities in epigenetic metabolic regulation (23,33,55,65).…”

Influence of Maternal Obesity on Insulin Sensitivity and Secretion in Offspring

“…A higher susceptibility of the female progeny to epigenetic insults has been already recognized in animals (20,21). To explain this sexual dimorphism, it has been hypothesized that the differential susceptibility to complex diseases, such as obesity and diabetes, in men and women is mediated by differences in the epigenetic regulation of genes induced by sex hormones (22).…”