Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover

A recently identified function of leptin is to protect nonadipose tissues f rom the nonoxidative metabolic products of long-chain fatty acids (FAs) dur ing periods of overnutrition by increasing the beta -oxidative metabolism o f surplus FAs and reducing lipogenesis. When this protective system fails, harmful products of nonoxidative metabolism such as ceramide increase in no nadipose tissues, including the pancreatic islets and heart, and cause nitr ic oxide-mediated lipotoxicity and lipoapoptosis. The triacylglycerol conte nt in nonadipocytes provides a useful index of overall nonoxidative metabol ism. In normal animal tissue triacylglycerol is maintained within a narrow range; even when the caloric intake is excessive, compensatory FA-induced u pregulation of oxidation prevents overaccumulation. However, if leptin is d eficient or if leptin receptors (Ob-R) are nonfunctional, this autoregulato ry 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 tissue s. FA overload in skeletal muscle causes insulin resistance; in myocardium, it impairs cardiac function; and in pancreatic islets, it causes beta -cel l dysfunction, apoptosis, and diabetes. All abnormalities in these tissues can be blocked by troglitazone, an inhibitor of FA accumulation.