Perinatal free-choice of a high-calorie low-protein diet affects leptin signaling through IRS1 and AMPK dephosphorylation in the hypothalami of female rat offspring in adulthood.

Aim: We aimed to investigate whether a dysregulated maternal diet during gestation and lactation induces long-lasting changes in the hypothalamic control of feeding behavior in the offspring and whether this effect is sex specific.

Methods: The study included an analysis of appetite-regulating metabolic hormones and hypothalamic signaling in male and female offspring in adulthood after exposure to a free-choice high-calorie palatable low-protein (P) diet or standard chow (C) during (pre)gestation/lactation (maternal) and/or postweaning (offspring).

Results: Maternal exposure to the P diet resulted in decreased protein intake and body weight gain in dams and decreased body weight gain in offspring during lactation. The maternal P diet (PC) specifically increased feed efficacy and decreased body weight and cholesterol levels in the female offspring in adulthood, but no changes in adiposity or leptin levels were found. In contrast, P diet exposure after weaning (CP and PP) increased caloric intake, adiposity and circulating levels of leptin in the male and female offspring in adulthood. The hypothalami of the female offspring exposed to the maternal P diet (PC and PP) expressed high levels of the phospho-leptin receptor and low levels of SOCS3, phospho-IRS1 and phospho-AMPK, regardless of the postweaning diet. The hypothalami of the female rats in the PC group also showed increased levels of STAT3 and the orexigenic neuropeptide Agrp.

Conclusions: Maternal exposure to a free-choice high-calorie low-protein diet induces a long-term feed efficacy associated with changes in leptin signaling through IRS-1 and AMPK dephosphorylation in the hypothalami of female offspring in adulthood.