Maternal High-Protein and Low-Protein Diets Perturb Hypothalamus and Liver Transcriptome and Metabolic Homeostasis in Adult Mouse Offspring

Early life nutritional imbalances are risk factors for metabolic dysfunctions in adulthood, but the long term effects of perinatal exposure to high versus low protein diets are not completely understood. We exposed C57BL/6J offspring to a high protein/low carbohydrate (HP/LC) or low protein/high carbohydrate (LP/HC) diet during gestation and lactation, and measured metabolic phenotypes between birth and 10 months of age in male offspring. Perinatal HP/LC and LP/HC exposures resulted in a decreased ability to clear glucose in the offspring, with reduced baseline insulin and glucose concentrations in the LP/HC group and a reduced insulin response post-glucose challenge in the HP/LC group. The LP/HC diet group also showed reduced birth and weanling weights, whereas the HP/LC offspring displayed increased weanling weight with increased adiposity beyond 5 months of age. Gene expression profiling of hypothalamus and liver revealed alterations in diverse molecular pathways by both diets. Specifically, hypothalamic transcriptome and pathway analyses demonstrated perturbations of MAPK and hedgehog signaling, processes associated with neural restructuring and transmission, and phosphate metabolism by perinatal protein imbalances. Liver transcriptomics revealed changes in purine and phosphate metabolism, hedgehog signaling, and circadian rhythm pathways. Our results indicate maternal protein imbalances perturbing molecular pathways in central and peripheral metabolic tissues, thereby predisposing the male offspring to metabolic dysfunctions.