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Previous studies suggested that norepinephrine inhibits proopiomelanocortin (POMC) neurons of the arcuate nucleus via \u03b12a\u2010adrenoceptors (ADRA2A), but the underlying mechanisms and physiological relevance of this pathway were not assessed. We therefore investigated how ADRA2 activation regulates POMC neuron activity and whether\n                    <jats:italic>Adra2a<\/jats:italic>\n                    expressed in POMC neurons contributes to energy and glucose homeostasis in vivo. We used whole\u2010cell patch clamp electrophysiology in male and female mice to evaluate the impact of norepinephrine and the ADRA2 agonist UK 14,304 on definitive POMC neurons in the arcuate nucleus. We also generated and validated a novel\n                    <jats:italic>Adra2a<\/jats:italic>\n                    \u2010flox mouse line, which was crossed with\n                    <jats:italic>Pomc<\/jats:italic>\n                    \u2010CreERT2 mice to produce inducible POMC\u2010specific\n                    <jats:italic>Adra2a<\/jats:italic>\n                    knockout mice (POMC\n                    <jats:sup>KOA2A<\/jats:sup>\n                    ). These mice were used for both electrophysiological analyses and in vivo assessment of energy and glucose homeostasis. Multiplex RNAscope confirmed that\n                    <jats:italic>Adra2a<\/jats:italic>\n                    was highly expressed in ~50% of POMC neurons, with significantly higher expression in females. Norepinephrine and the selective ADRA2 agonist UK 14,304 robustly inhibited POMC neurons in hypothalamic slices, producing hyperpolarization, reduced firing, and decreased input resistance independent of sex. These effects were mediated in part by activation of multiple potassium conductances, as blockade of K\n                    <jats:sub>ir<\/jats:sub>\n                    and K\n                    <jats:sub>ATP<\/jats:sub>\n                    channels attenuated the response. They were also partly indirect, as blockade of synaptic transmission reduced the proportion of neurons that were inhibited. Deletion of\n                    <jats:italic>Adra2a<\/jats:italic>\n                    in definitive POMC neurons had little effect on body weight, food intake, or adiposity, but modestly impaired glucose tolerance in males. Electrophysiological studies revealed that loss of\n                    <jats:italic>Adra2a<\/jats:italic>\n                    in POMC neurons prevented UK 14,304\u2010induced inhibition in approximately half of POMC neurons, supporting the involvement of both direct and indirect effects of UK 14,304 on POMC neuron activity. In conclusion, ADRA2A robustly inhibits hypothalamic POMC neurons through both direct and indirect mechanisms. However,\n                    <jats:italic>Adra2a<\/jats:italic>\n                    expression in POMC neurons is largely dispensable for the regulation of energy balance. These findings suggest that noradrenergic inhibition of POMC neuron activity involves additional cellular targets or network\u2010level pathways beyond POMC neurons themselves.\n                  <\/jats:p>","DOI":"10.1111\/jne.70169","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T06:06:28Z","timestamp":1774418788000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Noradrenergic inhibition of definitive\n                    <scp>POMC<\/scp>\n                    neurons through direct and indirect mechanisms"],"prefix":"10.1111","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0545-6993","authenticated-orcid":false,"given":"Olivier","family":"Lavoie","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy Universit\u00e9 Laval  Quebec City Quebec Canada"},{"name":"Quebec Heart and Lung Institute  Quebec City Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Audrey","family":"Turmel","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Universit\u00e9 Laval  Quebec City Quebec Canada"},{"name":"Quebec Heart and Lung Institute  Quebec City Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4498-7286","authenticated-orcid":false,"given":"Axelle","family":"Khouma","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Universit\u00e9 Laval  Quebec City Quebec Canada"},{"name":"Quebec Heart and Lung Institute  Quebec City Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moein","family":"Minbashi Moeini","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Universit\u00e9 Laval  Quebec City Quebec Canada"},{"name":"Quebec Heart and Lung Institute  Quebec City Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Hypothalamic Research, Department of Internal Medicine UT Southwestern Medical Center  Dallas Texas USA"},{"name":"Department of Neuroscience UT Southwestern Medical Center  Dallas Texas USA"},{"name":"Peter O'Donnell Jr. Brain Institute UT Southwestern Medical Center  Dallas Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9032-0862","authenticated-orcid":false,"given":"Natalie J.","family":"Michael","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Universit\u00e9 Laval  Quebec City Quebec Canada"},{"name":"Quebec Heart and Lung Institute  Quebec City Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6939-6136","authenticated-orcid":false,"given":"Alexandre","family":"Caron","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Universit\u00e9 Laval  Quebec City Quebec Canada"},{"name":"Quebec Heart and Lung Institute  Quebec City Quebec 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