A recently identified function of leptin is to protect nonadipose tissues from the nonoxidative metabolic products of long-chain fatty acids (FAs) during periods of overnutrition by increasing the beta-oxidative metabolism of surplus FAs and reducing lipogenesis. When this protective system fails, harmful products of nonoxidative metabolism such as ceramide increase in nonadipose tissues, including the pancreatic islets and heart, and cause nitric oxide-mediated lipotoxicity and lipoapoptosis. The triacylglycerol content in nonadipocytes provides a useful index of overall nonoxidative metabolism. In normal animal tissue, triacylglycerol is maintained within a narrow range; even when the caloric intake is excessive, compensatory FA-induced upregulation of oxidation prevents overaccumulation. However, if leptin is deficient or if leptin receptors (Ob-R) are nonfunctional, this autoregulatory system does not operate, and triacylglycerol content rises in nonadipose tissues. This provides a source of excess FAs that enter potentially toxic pathways of nonoxidative metabolism leading to apoptosis of certain tissues. FA overload in skeletal muscle causes insulin resistance; in myocardium, it impairs cardiac function; and in pancreatic islets, it causes beta-cell dysfunction, apoptosis, and diabetes. All abnormalities in these tissues can be blocked by troglitazone, an inhibitor of FA accumulation.