A Short‐Term Transition from a High‐Fat Diet to a Normal‐Fat Diet Before Pregnancy Exacerbates Female Mouse Offspring Obesity

Background/Objectives Recent findings have highlighted the detrimental influence of maternal over‐nutrition and obesity on fetal development and early life development. However, there are no evidence‐based guidelines regarding the optimal strategy for dietary intervention prior to pregnancy. Subjects/Methods We used a murine model to study whether switching from a high‐fat diet to a normal‐fat diet (H1N group) 1 week before pregnancy could lead to in utero reprogramming of female offspring obesity; comparator groups were offspring given a consistent maternal high‐fat diet (HF group) or normal‐fat diet (NF group) until weaning. After weaning, all female offspring were given the high‐fat diet for either 9 or 12 weeks before killed humanely. Results H1N treatment did not result in maternal weight loss before pregnancy. NF offspring were neither obese nor glucose‐intolerant during the entire experimental period. H1N offspring were most obese after the 12‐week postweaning HF diet and displayed glucose intolerance earlier than HF offspring. Our mechanistic study showed reduced adipocyte IRS1 and hepatic IRS2 expression and increased adipocyte p‐Ser 636/639 and p‐Ser 612 of H1N or HF offspring than in NF offspring. Among all groups, the H1N offspring had lowest level of IRS1 and the highest levels of p‐Ser 636/639 and p‐Ser 612 in gonadal adipocyte. In addition, H1N offspring further reduced expression of Glut4 and Glut2, versus those of HF offspring which was lower than NF offspring. There were also enhanced expression of genes inhibiting glycogenesis and decreased hepatic glycogen in H1N versus HF or NF offspring. Furthermore, we showed extremely higher expression of lipogenesis and adipogenesis genes in gonadal adipocytes of H1N offspring comparing to all other groups. Conclusion Our results suggest that a transition from a high‐fat diet to a normal‐fat diet shortly before pregnancy, without resulting in maternal weight loss, is not necessarily beneficial and may have deleterious effects on offspring. Support or Funding Information This project was supported by grants from the National Institutes of Health (NIH‐1R15HL117238 to LX and National Center for Research Resources, 5P20RR016471‐12/8 P20 GM103442‐12 to LX and KZ) and the American Heart Association (Scientist Development Grant13SDG14650009 to LX).