Metaflammation's Role in Systemic Dysfunction in Obesity: A Comprehensive Review.

Obesity is redefined as a complex systemic disease, transcending mere caloric imbalance, driven by intricate dysregulation across metabolic, neuroendocrine, immunological, and epigenetic axes. Central to its pathology is adipose tissue, which is considered a dynamic endocrine and immune organ. Its dysfunctional expansion fuels chronic, low-grade systemic inflammation, termed "metaflammation", characterised by pathways such as NF-kB and NLRP3 inflammasome activation, as well as pervasive immune cell infiltration. This inflammatory state could profoundly impair insulin signalling and contribute to major complications, including insulin resistance, type 2 diabetes, and cardiovascular disease. Further exacerbating this systemic dysfunction is gut microbiota dysbiosis, which promotes metabolic endotoxemia and neuroendocrine dysregulation, impacting hypothalamic function, central hormone resistance, and reproductive health. Epigenetic modifications also serve as crucial mediators, translating environmental exposures into altered gene expression that perpetuates susceptibility across generations. This review summarises the current understanding of obesity by integrating molecular, neuroendocrine, and immunometabolic underpinnings, reinterpreting it as a comprehensive expression of systemic dysfunction. Through this integrated perspective our hope is to highlight the necessity of a paradigm shift towards personalised, multi-targeted interventions that extend beyond conventional weight management. An integrative, translational approach modulating the immunometabolic network, microbiota, and epigenetics is essential to effectively address the global obesity epidemic and its far-reaching health implications.