<p>White adipose tissue (WAT) is a remarkably plastic organ integrating metabolic, endocrine and immune functions. In humans, perturbations in adipocyte turnover, size regulation and cellular heterogeneity underpin the transition from metabolic health to obesity-related disease. This review, based on the 2025 Camillo Golgi Prize Lecture, highlights selected mechanistic and translational insights, primarily from our work and that of close collaborators, that have contributed to reshaping our understanding of human adipose biology. ¹⁴C-dating and clinical studies demonstrate that adipocytes are continuously renewed, and that impaired lipid turnover predisposes to weight gain, insulin resistance and type 2 diabetes. Obesity induces persistent transcriptional and structural alterations, an ‘adipose memory’, that provides a biological basis for understanding the difficulty of maintaining weight loss. Spatial transcriptomics has revealed at least three major adipocyte states in human WAT that differ in insulin responsiveness and lipid-handling capacity, suggesting that adipocyte composition influences depot function and responsiveness to interventions such as weight loss or pharmacological therapies. In addition, depot-specific enrichment of immunomodulatory adipocytes, particularly in epiploic WAT, highlights local adipocyte–immune crosstalk as a contributor to systemic inflammation. Collectively, these advances redefine human WAT as an active driver of cardiometabolic disease and highlight therapeutic strategies targeting adipocyte plasticity and immune–metabolic interactions.</p> Graphical Abstract <p></p>