Differential Responses of Orexigenic Neuropeptides to Fasting in Offspring of Obese Mothers

Abstract

Maternal obesity due to long-term high-fat diet (HFD) consumption leads to faster growth in offspring during suckling, and increased adiposity at 20 days of age. Decreased expression of the orexigenic neuropeptide Y (NPY) and increased anorexigenic proopiomelanocortin (POMC) mRNA expression were observed in the fed state. However, hunger is the major drive to eat and hypothalamic appetite regulators change in response to meals. Therefore, it is important to compare both satiated and fasting states. Female Sprague-Dawley rats (8 weeks old) were fed a cafeteria-style HFD (15.33 kJ/g) or chow for 5 weeks before mating, with the same diet continuing throughout gestation and lactation. At postnatal day 20, male pups were killed either after overnight fasting or in the fed state. Pups from obese dams were hyperphagic during both pre- and postweaning periods. Pups from obese dams had higher hypothalamic mRNA expression of POMC and NPY Y1 receptor, but lower hypothalamic melanocortin-4 receptor (MC4R) and its downstream target single-minded gene 1 (Sim1), in the fed state. Overnight fasting reduced circulating glucose, insulin, and leptin and increased hypothalamic NPY Y1 receptor mRNA in pups from both lean and obese dams. Hypothalamic NPY and agouti-related protein (AgRP) were only increased by fasting in pups from obese dams; reductions in MC4R and Sim1 were only seen in pups from lean dams. At weaning, the suppressed orexigenic signals in offspring from obese dams were normalized after overnight fasting, although anorexigenic signaling appeared impaired in these animals. This may contribute to their hyperphagia and faster growth.