Paternal lactational overnutrition induces sex-dependent hypothalamic neuropeptide programming in offspring

Childhood obesity can induce long-lasting metabolic programming, with consequences that may extend to subsequent generations. However, whether paternal early-life obesity programs hypothalamic neuropeptide pathways controlling feeding behavior in offspring remains poorly understood. We investigated the effects of paternal obesity induced by lactational overnutrition on hypothalamic neuropeptide expression, circulating leptin, and food intake in adult offspring. On postnatal day (PND) 0, male Wistar rats were assigned to normal litters (NL; 10 pups/dam) or small litters (SL; 3 pups/dam) to induce lactational overnutrition and early obesity. At PND 90, NL and SL males were mated with control females to generate F1 offspring. In adulthood, hypothalamic mRNA expression of the orexigenic neuropeptides neuropeptide Y (NPY) and agouti-related peptide (AgRP) and the anorexigenic neuropeptides proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART), as well as plasma leptin concentrations and food intake, were evaluated. Male offspring of SL fathers exhibited reduced hypothalamic mRNA expression of NPY, AgRP, POMC, and CART compared with offspring of NL fathers. These alterations were accompanied by reduced cumulative food intake and lower plasma leptin concentrations. In contrast, no significant differences were observed in female offspring. These findings demonstrate that paternal obesity induced by lactational overnutrition is associated with sex-dependent neuroendocrine programming in the next generation, characterized by coordinated remodeling of hypothalamic orexigenic and anorexigenic neuropeptide pathways. This hypothalamic neuropeptide remodeling may contribute to the altered feeding phenotype observed in male offspring and represents a potential central target of paternal metabolic programming.