{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:12:25Z","timestamp":1790359945125,"version":"4.1.0"},"reference-count":132,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"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. Immunol."],"abstract":"<jats:p>\n                    Obesity and chronic pain co-occur at high rates, yet the mechanistic logic that connects metabolic excess to persistent nociception remains fragmented across separate literatures. This review integrates these literatures around a single guiding question: how does chronic energy overload become a sensitized nervous system that no longer self-terminates? We propose a Metabolic\u2013Immune\u2013Neural (MIN) triangle hypothesis and trace a four-step causal chain. First, adipose tissue remodeling\u2014hypertrophy, hypoxia, ER stress, lipid spillover, and metabolic endotoxemia\u2014generates the molecular precursors of inflammation. Second, immune-cell remodeling and immunometabolic reprogramming amplify these signals, and trained immunity inscribes an epigenetic memory in myeloid cells and adipocytes that survives weight loss. Third, adipocyte\u2013macrophage positive feedback loops, failed biosynthesis of specialized pro-resolving mediators (SPMs), and defective efferocytosis prevent resolution, so systemic low-grade chronic inflammation persists. Fourth, these signals converge on a three-tier sensitization cascade\u2014peripheral (DRG neuro-immune unit), spinal (microglial\u2013astrocytic disinhibition and NMDA-LTP), and supraspinal (descending-control imbalance with vagal\u2013HPA brake failure)\u2014producing four clinically tractable phenotypes: metabolic osteoarthritis, diabetic small-fiber neuropathy, mixed-mechanism low back pain, and sex-dimorphic pain. This framework supports a precision-medicine strategy in which NLRP3 and Na\n                    <jats:sub>v<\/jats:sub>\n                    1.8 inhibitors, SPM analogs, GLP-1 receptor agonists, vagus nerve stimulation, and epigenetic modulators can be combined according to a patient\u2019s metabolic\u2013immune phenotype. We position obesity-related chronic pain not as a universal \u201cterminal complication\u201d of metabolic disease, but as a frequent and mechanistically explicable consequence of unresolved metabolic inflammation\u2014one in which the depth of sensitization, rather than weight loss alone, defines therapeutic outcome.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1889437","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:00:36Z","timestamp":1785402036000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Obesity-driven low-grade chronic inflammation as a mechanistic bridge to chronic pain: from adipose tissue remodeling to central sensitization"],"prefix":"10.3389","volume":"17","author":[{"given":"Yi-xin","family":"Ma","sequence":"first","affiliation":[{"name":"Liaoning University of Traditional Chinese Medicine","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Lin","sequence":"additional","affiliation":[{"name":"Liaoning University of Traditional Chinese Medicine","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Nan","sequence":"additional","affiliation":[{"name":"Liaoning University of Traditional Chinese Medicine","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan-nan","family":"Li","sequence":"additional","affiliation":[{"name":"Liaoning University of Traditional Chinese Medicine","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Liu","sequence":"additional","affiliation":[{"name":"Liaoning University of Traditional Chinese Medicine","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao-ran","family":"Wang","sequence":"additional","affiliation":[{"name":"Liaoning University of Traditional Chinese Medicine","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun-yu","family":"Ning","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Liaoning University of Traditional Chinese Medicine","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Zhang","sequence":"additional","affiliation":[{"name":"Liaoning University of Traditional Chinese Medicine","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(23)02750-2","article-title":"Worldwide trends in underweight and obesity from 1990 to 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