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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\u2009weeks. Body weight, naso\u2010anal 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\u2010IR). CAF promotes caloric and nutritional efficiency increase, regardless of the situation in early\u2010life. SL\u2010CAF 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\u2010opiomelanocortin (\n                    <jats:italic>Pomc<\/jats:italic>\n                    ) expression in ARC, potentially linked to promoter and enhancer hypermethylation. On the other hand, Neuropeptide Y (\n                    <jats:italic>Npy<\/jats:italic>\n                    ) 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\u2010life 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\u2013brain interactions in obesity.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70449-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70449","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T12:01:11Z","timestamp":1777032071000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Neonatal Overnutrition Induces Long\u2010Lasting Hypothalamic\n                    <scp>POMC<\/scp>\n                    Silencing and Shapes Distinct Obesity Phenotypes According to Adult Dietary Environments"],"prefix":"10.1111","volume":"170","author":[{"given":"Pamela Roc\u00edo","family":"Fern\u00e1ndez","sequence":"first","affiliation":[{"name":"Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioqu\u00edmica y Ciencias Biol\u00f3gicas Universidad Nacional del Litoral\u2010CONICET  Santa Fe Argentina"},{"name":"C\u00e1tedra de Nutrici\u00f3n en Situaciones Patol\u00f3gicas, Facultad de Bioqu\u00edmica y Ciencias Biol\u00f3gicas Universidad Nacional del Litoral  Santa Fe Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2506-4801","authenticated-orcid":false,"given":"Luisa","family":"Gaydou","sequence":"additional","affiliation":[{"name":"Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioqu\u00edmica y 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