Abstract

Obesity-induced type 2 diabetes (T2D) is not simply a problem of “too much fat” but of where lipid ends up and 
how it moves between organs. Under physiological conditions, subcutaneous adipose tissue (AT) serves as a safe 
reservoir that buffers postprandial lipid flux, limiting exposure of non-adipose organs to toxic lipid 
intermediates. In obesity, however, AT becomes inflamed, fibrotic, and relatively non-expandable, leading to 
adipose overflow: excess fatty acids and triglyceride-rich lipoproteins spill into the circulation and are deposited 
as ectopic fat in liver, skeletal muscle, pancreas, heart, and kidney.Within these organs, neutral triglyceride 
storage in lipid droplets coexists with accumulation of bioactive lipids such as diacylglycerols (DAGs) and 
ceramides that interfere with insulin signaling, mitochondrial function, and cell survival, a process termed 
lipotoxicity. Lipid-induced stress triggers maladaptive inter-organ crosstalk mediated by adipokines, 
hepatokines, myokines, and extracellular vesicles, amplifying insulin resistance and β-cell failure. This review 
frames obesity-induced diabetes as a network disease of disordered lipid trafficking. We first outline the adipose 
tissue expandability and overflow hypotheses, then detail how ectopic lipid accumulation and lipotoxic 
intermediates drive insulin resistance and dysfunction in liver, muscle, pancreas, and heart. We next highlight 
emerging roles for organokines and extracellular vesicles in lipid-related signaling between tissues. Finally, we 
discuss therapeutic strategies that re-route lipid flux through improving adipose storage capacity, targeting 
ceramide and DAG synthesis, or altering lipoprotein handling and future biomarker and fluxomic approaches 
that may enable precision management of lipotoxic diabetes.