Prometheus’s Fire, Part I: The Flight of Icarus—Molecular Mechanisms Underlying Adipose Tissue Dysfunction in Obesity: From Adaptive Hyperplasia to Pathological Hypertrophy

Obesity is a heterogeneous disease in which cardiometabolic risk is shaped not only by adipose tissue mass but also by the capacity of adipose tissue to expand and remain metabolically functional. This narrative review provides an integrated, evidence-weighted molecular framework, the central original contribution of this work, for understanding how initially adaptive adipose tissue expansion transitions into pathological hypertrophy and self-sustaining immunometabolic dysfunction. We examine how impaired adipogenesis, angiogenesis and extracellular-matrix remodelling converge with mitochondrial and endoplasmic reticulum stress, oxidative stress, hypoxia and lipotoxicity to destabilise adipocyte homeostasis. Particular attention is given to the NLRP3 inflammasome, positioned within a broader network including JNK, IKKβ/NF-κB, TLR4 and cGAS–STING signalling, as a molecular integrator of metabolic danger signals. We further explore how adipokine remodelling, loss of adiponectin-mediated protection and enhanced leptin signalling interact with immune-cell recruitment to establish self-amplifying inflammatory circuits. Evidence is stratified across experimental, translational and human levels; a summary table maps each mechanism to its strength of evidence and current clinical relevance. This framework explains metabolic phenotype heterogeneity among individuals with comparable adiposity and establishes the molecular foundation for Parts II and III of the Prometheus’s Fire series.