Neonatal Overnutrition Induces Long-Lasting Hypothalamic POMC Silencing and Shapes Distinct Obesity Phenotypes According to Adult Dietary Environments.

Our study aimed to analyze the individual effects of early-life overnutrition (focusing on its long-lasting impact) and adult cafeteria diet (CAF) exposure, as well as their combined effect, on hypothalamic food-intake regulation. Neonatal overfeeding was induced by a small litter model (SL, 4 pups/dam), and the control group was raised in normal litters (NL, 10 pups/dam). Male rats received control diet (CON) until postnatal day (PND) 90 and then CON or CAF for 11 weeks. Body weight, naso-anal length and food intake were recorded weekly. At PND167, rats were euthanized to obtain brain, blood and fat pads. Arcuate Nucleus (ARC) was isolated by micropunch technique for qPCR analysis. Hypothalamic gene expression and DNA methylation were analyzed. Neonatal overfeeding and/or adult CAF diet exposure drive obesity development, hyperinsulinemia and altered Homeostatic Model Assessment (HOMA-IR). CAF promotes caloric and nutritional efficiency increase, regardless of the situation in early-life. SL-CAF rats exhibited impaired feeding behavior characterized by a higher standard chow consumption over the palatable foods. At transcriptional level, early overnutrition was associated with lasting reduced Pro-opiomelanocortin (Pomc) expression in ARC, potentially linked to promoter and enhancer hypermethylation. On the other hand, Neuropeptide Y (Npy) expression is decreased by neonatal overnutrition, apparently responding to peripheral stimuli. Leptin receptor expression is reduced by the CAF diet, suggesting a mechanism of leptin resistance. Our research reveals distinct obesity phenotypes, each with specific molecular, epigenetic, and behavioral characteristics. These findings highlight the need for tailored therapeutic strategies that account for these mechanistic differences. Importantly, early-life overnutrition alters hypothalamic regulatory circuits with lasting effects. Together, our findings show how nutritional experiences across the lifespan shape hypothalamic neurochemistry, advancing our understanding of feeding-brain interactions in obesity.