{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:44:17Z","timestamp":1791859457365,"version":"4.3.4"},"reference-count":122,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Overweight and obesity have emerged as global health crises and are increasingly recognized as drivers of central nervous system (CNS) dysfunction. Beyond excess energy storage, white adipose tissue (WAT) functions as an active endocrine and immune organ that, during obesity, undergoes inflammatory remodeling and releases cytokines, lipid mediators, adipokines, and extracellular vesicles that influence brain physiology. These peripheral signals disrupt key brain interfaces, including the blood-brain barrier (BBB), perivascular and glymphatic clearance pathways, promoting endothelial dysfunction, altered astrocyte-pericyte support, impaired amyloid-\u03b2 clearance, and region-specific glial activation. Obesity-associated neuroinflammation is characterized by microglial priming and astrocyte reactivity across the hypothalamus, hippocampus, and other circuits governing metabolism, cognition, and reward, with growing evidence for sex-dependent vulnerability. We further highlight adipokines as key mediators of adipose-brain communication. In obesity, leptin resistance impairs central energy regulation, reduced adiponectin contributes to neuroinflammation and synaptic dysfunction, and elevated resistin enhances TLR4-dependent inflammatory signaling and BBB permeability, collectively linking metabolic stress to neurodegenerative processes. Finally, we review therapeutic strategies targeting the adipose-brain axis, including exercise and dietary interventions that improve neuroplasticity and barrier integrity, and pharmacological approaches such as orlistat and incretin-based therapies. Emerging multi-incretin agonists, including tirzepatide and retatrutide, raise important questions regarding direct CNS actions beyond metabolic benefits, underscoring the need to integrate barrier biology and neuroimmune mechanisms in future studies.<\/jats:p>","DOI":"10.3389\/fphys.2026.1795058","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T13:06:51Z","timestamp":1775826411000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Metabolic inflammation at the adipose-brain axis"],"prefix":"10.3389","volume":"17","author":[{"given":"Saudina","family":"Mateus-Gomes","sequence":"first","affiliation":[{"name":"Centre d\u2019Immunologie de Marseille-Luminy, Centre national de la recherche scientifique (CNRS) Institut national de la sant\u00e9 et de la recherche m\u00e9dicale (INSERM), Aix Marseille Universit\u00e9","place":["Marseille, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amnah","family":"Al-Sayyar","sequence":"additional","affiliation":[{"name":"Centre d\u2019Immunologie de Marseille-Luminy, Centre national de la recherche scientifique (CNRS) Institut national de la sant\u00e9 et de la recherche m\u00e9dicale (INSERM), Aix Marseille Universit\u00e9","place":["Marseille, France"]},{"name":"Immunology & Microbiology Department, Dasman Diabetes Institute","place":["Kuwait, Kuwait"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baptiste","family":"Lobey","sequence":"additional","affiliation":[{"name":"Centre d\u2019Immunologie de Marseille-Luminy, Centre national de la recherche scientifique (CNRS) Institut national de la sant\u00e9 et de la recherche m\u00e9dicale (INSERM), Aix Marseille Universit\u00e9","place":["Marseille, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnes","family":"Nadjar","sequence":"additional","affiliation":[{"name":"Institute of Neurodegenerative Diseases, Centre national de la recherche scientifique (CNRS) UMR-5293, University of Bordeaux","place":["Bordeaux, France"]},{"name":"Institut Universitaire de France (IUF)","place":["Paris, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rejane","family":"Rua","sequence":"additional","affiliation":[{"name":"Centre d\u2019Immunologie de Marseille-Luminy, Centre national de la recherche scientifique (CNRS) Institut national de la sant\u00e9 et de la recherche m\u00e9dicale (INSERM), Aix Marseille Universit\u00e9","place":["Marseille, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasheed","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Immunology & Microbiology Department, Dasman Diabetes Institute","place":["Kuwait, Kuwait"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1841","DOI":"10.1093\/jn\/135.8.1841","article-title":"Palmitate activates the NF-\u03baB transcription factor and induces IL-6 and TNF\u03b1 expression in 3T3-L1 adipocytes","volume":"135","author":"Ajuwon","year":"2005","journal-title":"J. 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