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While work in Drosophila has identified functionally overlapping enhancers, work in mammalian models has been limited. Recently, we have identified two partially redundant enhancers, nPE1 and nPE2, that drive proopiomelanocortin gene expression in the hypothalamus. Here we demonstrate that deletion of nPE1 produces mild obesity while knockout of nPE2 has no discernible metabolic phenotypes. Additionally, we show that acute leptin administration has significant effects on nPE1 knockout mice, with food intake and body weight change significantly impacted by peripheral leptin treatment. nPE1 knockout mice became less responsive to leptin treatment over time as percent body weight change increased over 2 week exposure to peripheral leptin. Both <jats:italic>Pomc<\/jats:italic> and <jats:italic>Agrp<\/jats:italic> mRNA were not differentially affected by chronic leptin treatment however we did see a decrease in <jats:italic>Pomc<\/jats:italic> and <jats:italic>Agrp<\/jats:italic> mRNA in both nPE1 and nPE2 knockout calorie restricted mice as compared to calorie restricted PBS-treated WT mice. Collectively, these data suggest dynamic regulation of <jats:italic>Pomc<\/jats:italic> by nPE1 such that mice with nPE1 knockout become less responsive to the anorectic effects of leptin treatment over time. Our results also support our earlier findings in which nPE2 may only be critical in adult mice that lack nPE1, indicating that these neural enhancers work synergistically to influence metabolism.<\/jats:p>","DOI":"10.1371\/journal.pone.0244793","type":"journal-article","created":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T20:47:37Z","timestamp":1609447657000},"page":"e0244793","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Decreased sensitivity to the anorectic effects of leptin in mice that lack a Pomc-specific neural enhancer"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7236-9868","authenticated-orcid":true,"given":"Elisa S.","family":"Na","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8593-3157","authenticated-orcid":true,"given":"Daniel 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