Excess fat in peripheral tissues can result in insulin insensitivity. Excess fat accumulation in peripheral tissues, most notably muscle, can disrupt some signal-transduction pathways and inappropriately activate others. In particular, diacylglycerols and ceramide activate stress-induced pathways that interfere with insulin signaling, resulting in insulin resistance. (Abbreviations: DAG, diacylglycerol; TGs, triacylglycerols; ROS, reactive oxygen species; CA1, carnitine acyltransferase 1; GLUT4, glucose transporter 4; IR, insulin receptor; ETC, electron-transport chain; TCA, tricarboxylic acid cycle.)