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Deficiency of CNS LepR or MC4R signaling causes severe obesity and is accompanied by multiple metabolic abnormalities including insulin resistance, glucose intolerance, and hyperlipidemia that are only partially explained by obesity. Defective LepR and MC4R signaling also causes dysfunction of the sympathetic nervous system (SNS) and blood pressure (BP) regulation. Hyperleptinemia and activation of the CNS melanocortin system in obesity are important compensatory mechanisms that attenuate abnormalities of glucose and lipid metabolism but may also contribute to SNS activation and increased BP. Despite potentially adverse effects of increases in SNS activity and BP, pharmacological activation of brain LepRs and MC4Rs may provide an important therapeutic approach for protecting target organs, such as the heart, kidneys, and brain, from ischemic injury by improving mitochondrial function and ATP production. However, additional preclinical studies are needed to address mechanistic questions before clinical studies are begun to test the effectiveness of leptin and MC4R agonists for treating people with ischemic injury of target organs.<\/jats:p>","DOI":"10.1042\/cs20250039","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T11:32:14Z","timestamp":1782300734000},"page":"1473-1496","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cardiometabolic regulation by adipocyte-derived leptin and the brain melanocortin system"],"prefix":"10.1042","volume":"140","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9867-5855","authenticated-orcid":false,"given":"John\u00a0E.","family":"Hall","sequence":"first","affiliation":[{"name":"1Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, U.S.A."},{"name":"2Mississippi Center for Obesity Research, University 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