Fetal origins of disease: Essential nutrient supplementation prevents adult metabolic disease in a transgenerational model of IUGR


      Adult metabolic diseases, such as obesity and diabetes, result from in utero constraints; these morbidities have been shown to extend across generations. Development of the metabolic phenotype is associated with fetal alterations in one-carbon metabolism, which manifest as persistent changes in hepatic gene expression accompanied by epigenetic modifications in DNA methylation. We hypothesized that supplementation of essential nutrients (ENS) serving as intermediates in the one-carbon pathway would prevent adult metabolic disease. We therefore sought to characterize the effects of ENS in a transgenerational model of IUGR.

      Study design

      Sprague-Dawley P1 dams underwent bilateral uterine artery ligation (n 8) or sham surgery (n 8) on e19, and resultant F1 litters yielded IUGR (n 64) or control lineages (n 64), respectively. On d21, weaned F1 were allocated to ENS (Teklad8640+folic acid, choline, B12, betaine, L-methionine, L-arginine, zinc) or control diet (Teklad8640). F1 pairs were mated by d80, and resultant F2 (n 512) were weaned to their parental diet. F2 body composition was determined by pDEXA, and glucose and insulin tolerance tests with hyperinsulinemic euglycemic [14C]glucose clamps were performed.


      Significant differences in mean birthweight were observed among F2 offspring of IUGR lineages (maternal 6.1 g, paternal 6.5 g, both 5.6 g) when compared with shams (8.0 g), regardless of maternal diet (6.0 g vs 6.1 g). However, by d160 these progeny of IUGR animals on control diet exceeded sham body weights (496 g vs 411 g) while ENS fed had not (340 g vs 390 g). Central fat mass was significantly less among ENS fed IUGR lineages (7.9 g vs 53.5 g, p=.02). Furthermore, male offspring from the IUGR lineages on control diet developed hepatic insulin resistance (HGO 9.5 vs −.2 mg/kg/min, p=.02), wherease the ENS diet prevented this adult morbidity (1.5 mg/kg/min, p=.047).


      Diet supplemented with essential nutrients, yet unaltered in its caloric content, prevents adult obesity and insulin resistance in a heritable transgenerational model of IUGR.