A methyl-deficient diet fed to rat dams during the peri-conception period programs glucose homeostasis in adult male but not female offspring

Abstract

Methyl deficiencies have been implicated in metabolic programming during the periods of oocyte and embryo development. Semisynthetic methyl-deficient diets (MD) with no folic acid, 0.05% choline, and approximately one-half the recommended content of methionine were fed to female rats for 3 wk prior to mating and for the first 5 d of gestation. During the period of MD feeding, plasma homocysteine concentrations were approximately twice those of rats fed the complete (CON) diet. From d 5, both groups received a complete semipurified AIN diet until birth. On d 8, plasma homocysteine concentrations did not differ between the 2 groups. Thereafter, dams and offspring were fed a nonpurified diet for the remainder of the experiment. At 6 mo of age, the homeostatic model assessment (HOMA) index of the male MD offspring tended to be 32% higher (P = 0.053) and peak insulin during an oral glucose tolerance test (oGTT) was 39% higher (P < 0.05) compared with the male CON offspring. There was no difference in the response to an oGTT in the female offspring at 6 mo of age. The increased HOMA index of male MD offspring persisted to 12 mo of age. The peak glucose concentration during oGTT was 23% higher (P < 0.05) in MD compared with the CON males despite 39% greater (P < 0.05) peak insulin concentrations. This study shows that in rats, a physiologically relevant methyl-deficient diet fed during the period of oocyte maturation and preimplantation development programs gender-specific changes in glucose handling by the offspring.

FIGURE 1

HOMA in male and female offspring of rats fed the CON or MD diet during the peri-conception period at 26 wk and in the male offspring at 51 wk of age. One male and one female pup from each litter was assessed at 26 wk (CON male, n = 18; CON female, n = 16; MD male, n = 17; MD female, n = 16). A second male pup from each litter was assessed at 51 wk (CON, n = 12; MD, n = 12). Data were analyzed with residual maximum likelihood, where the interactions between maternal diet and offspring sex or age formed the fixed effects and dam formed the random effect. Data are presented as predicted means ± SEM. At 6 mo, male offspring > female offspring (P < 0.001) and MD > CON (P = 0.053). For male offspring, 12 mo > 6 mo (P = 0.039) and MD > CON (P = 0.020).

FIGURE 2

Plasma glucose (A,B) and insulin concentrations (C,D) during OGTT in 26-wk-old male (A,C) and female (B,D) offspring of rats fed a CON or MD diet during the peri-conception period. Values are means ± SEM, n = 16–18. *Different from CON, P < 0.05.

FIGURE 3

Plasma glucose (A) and insulin (B) concentrations during the OGTT in 51-wk-old male offspring of rats fed CON or MD diet during the peri-conception period. Values are means ± SEM, n = 12 (1 pup/litter). *Different from CON, P < 0.05.