Prometheus’s Fire, Part III: The Forge of Hephaestus—Non-Pharmacological and Pharmacological Interventions Targeting Adipose Tissue Immunometabolism in Obesity

There is a growing recognition of obesity as a chronic immunometabolic disease in which impaired adipose tissue expandability contributes to a self-amplifying inflammatory network that extends across multiple organs. This state-of-the-art narrative review, the third and final part of the Prometheus’s Fire series, considers how lifestyle interventions, bariatric surgery and pharmacological therapies may disrupt this network and support the restoration of immunometabolic homeostasis. We introduce the concept of therapeutic convergence, describing how interventions with different primary mechanisms can influence shared processes, including NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activity, adipokine dysregulation, adipose tissue remodelling, mitochondrial stress and inter-organ inflammatory signalling. Evidence from randomised controlled trials, meta-analyses and mechanistic studies shows that these interventions differ considerably in the extent and breadth of their effects. Bariatric surgery, glucagon-like peptide-1 (GLP-1) receptor agonists and double GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists (tirzepatide) have the most consistent evidence for coordinated effects on adipose tissue inflammation, metabolic dysfunction and inter-organ signalling. Other interventions appear to influence more selected components of the network and may therefore have greater value as complementary rather than comprehensive approaches. This perspective also highlights a limitation of relying on body weight as the primary measure of therapeutic success. Weight loss remains an important clinical goal, but it may not fully reflect the extent or durability of immunometabolic recovery. The therapeutic convergence framework therefore offers a way to understand how mechanistically distinct interventions can produce overlapping systemic benefits and may help identify treatment strategies that more effectively restore adipose tissue function while disrupting the inflammatory processes that sustain metabolic disease.