{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T17:22:43Z","timestamp":1791912163823,"version":"4.3.4"},"reference-count":310,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The neuroendocrine and immune systems interact bidirectionally through shared ligands and receptors during inflammation, thereby regulating immune responses. Leptin, primarily known for its role in energy metabolism and appetite regulation, also modulates neuroinflammatory pathways. Its receptors are widely expressed on immune cells and contribute to immune mechanisms implicated in the pathogenesis of neuroinflammatory disorders such as multiple sclerosis (MS) and Alzheimer\u2019s disease (AD). This review highlights recent advances in understanding leptin\u2019s role in immune regulation, with a focus on its impact on MS and AD. A comprehensive literature review was conducted until October 2025, using PubMed, Google Scholar, and Scopus to identify studies investigating leptin in neuroinflammatory conditions, particularly MS and AD. Leptin exerts broad immunomodulatory effects by activating T cells, dendritic cells, and microglia, and promoting their proliferation and phagocytosis. Its elevation enhances Th1 and Th17 responses, drives pro-inflammatory macrophage phenotype polarization, and suppresses regulatory T cell and Th2 responses, immune pathways involved in MS. Peripheral leptin levels are increased in MS, especially during disease exacerbations. In contrast, in AD, they are typically reduced, particularly in patients with normal body mass index (BMI), where their decline contributes to amyloid-\u03b2 and tau pathology. These divergent patterns position leptin as a bidirectional regulator at the intersection of immunity and neurodegeneration. Additionally, its protective or detrimental effects likely depend on whether it acts under physiological conditions or in the context of obesity-induced leptin resistance. Elevated leptin levels in obesity exacerbate inflammation and diminish its neuroprotective effects. In conclusion, leptin is elevated in MS patients but downregulated in AD, reflecting its bidirectional effects. In leptin resistance, peripheral proinflammatory signaling is maintained while central leptin signaling is restricted, thereby potentially promoting autoimmunity in MS and limiting neuroprotection in AD. Further mechanistic and longitudinal studies are needed to clarify the relationship between leptin dysregulation, leptin resistance, neuroinflammatory and neurodegenerative diseases.<\/jats:p>","DOI":"10.3390\/ijms27010168","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T14:05:22Z","timestamp":1766498722000},"page":"168","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Leptin as a Potential Modifier of Neuroinflammation: Contrasting Roles in Alzheimer\u2019s Disease and Multiple Sclerosis"],"prefix":"10.3390","volume":"27","author":[{"given":"Naghmeh","family":"Abbasi Kasbi","sequence":"first","affiliation":[{"name":"Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5715-4567","authenticated-orcid":false,"given":"Barbara Elena","family":"Stopschinski","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Peter O\u2019Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Center for Alzheimer\u2019s and Neurodegenerative Diseases (CAND), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alanna Gabrielle","family":"Polyak","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Department of Biological Sciences, Dartmouth College, Hanover, NH 03755, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agastya Reddy","family":"Malladi","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Navid","family":"Manouchehri","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0680-3392","authenticated-orcid":false,"given":"Philipp E.","family":"Scherer","sequence":"additional","affiliation":[{"name":"Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf","family":"Stuve","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Peter O\u2019Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Neurology Section, VA North Texas Health Care System, Dallas, TX 75216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3971","DOI":"10.1074\/jbc.271.8.3971","article-title":"Genomic structure and promoter analysis of the human obese gene","volume":"271","author":"Gong","year":"1996","journal-title":"J. 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