Eighty Years After Vague: Advances in Understanding Ectopic Fat and Metabolic Dysfunction

The distribution of adipose tissue is a key determinant of obesity-related disease risk. When the capacity of subcutaneous adipose tissue to safely store energy is exceeded, lipid overflow into visceral depots occurs, increasing free fatty acid flux, promoting insulin resistance, and triggering chronic low-grade inflammation. More than 80 years ago, the physician Jean Vague recognized the association between android (central) obesity and cardiometabolic disease; subsequent advances from imaging technologies have expanded this framework to include ectopic fat accumulation within non-adipose organs. Ectopic fat deposition in the liver, pancreas, heart, kidneys, skeletal muscle, and upper airway contributes to organ-specific dysfunction through mechanisms including lipotoxicity, adipokine dysregulation, oxidative stress, and local inflammatory signaling. This review summarizes the evidence linking visceral and ectopic fat to metabolic dysfunction-associated steatotic liver disease and steatohepatitis, type 2 diabetes, cardiovascular and renal disease, sarcopenic obesity, and obstructive sleep apnea. Importantly, visceral and ectopic fat depots are modifiable. Lifestyle-induced energy deficit, incretin-based pharmacotherapy, and metabolic bariatric surgery reduce visceral and ectopic fat and improve glycemic control, liver fat content, cardiovascular risk factors, physical function, and sleep-disordered breathing. Incorporating ectopic fat characterization into clinical practice may enhance risk stratification and support more personalized management of obesity phenotypes.