Obesity-driven low-grade chronic inflammation as a mechanistic bridge to chronic pain: from adipose tissue remodeling...

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-Immune-Neural (MIN) triangle hypothesis and trace a four-step causal chain. First, adipose tissue remodeling-hypertrophy, hypoxia, ER stress, lipid spillover, and metabolic endotoxemia-generates 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-macrophage 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-peripheral (DRG neuro-immune unit), spinal (microglial-astrocytic disinhibition and NMDA-LTP), and supraspinal (descending-control imbalance with vagal-HPA brake failure)-producing 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_v1.8 inhibitors, SPM analogs, GLP-1 receptor agonists, vagus nerve stimulation, and epigenetic modulators can be combined according to a patient's metabolic-immune phenotype. We position obesity-related chronic pain not as a universal "terminal complication" of metabolic disease, but as a frequent and mechanistically explicable consequence of unresolved metabolic inflammation-one in which the depth of sensitization, rather than weight loss alone, defines therapeutic outcome.