Here we explore the physiologic role of leptin as a liporegulatory hormone responsible for maintaining intracellular homeostasis in the face of wide variations in caloric intake. Normally, rats can tolerate a 60% fat diet because 96% of the surplus fat is deposited in adipocytes. In contrast, when leptin is congenitally absent or inactive, even on a normal diet, unutilized dietary fat is deposited in nonadipose tissues, causing dysfunction (lipotoxicity) and possible cell death (lipoapoptosis). We theorize that in diet-induced obesity, acquired leptin resistance may also develop as the result of increase in certain leptin resistance factors. Acquired leptin resistance occurs in aging, obesity, Cushing's syndrome, and acquired lipodystrophy, and preliminary evidence suggests that ectopic lipid deposition is increased. We speculate that the metabolic syndrome may be the human equivalent of the lipotoxic syndrome of rodents.