For most of human evolution, the ability to store nutrients in the form of esterified lipids triacylglycerols (TAG) has constituted a survival advantage for times of famine and/or energy deficit. In more recent times, this “thrifty” fuel economy has been challenged by overconsumption of energy-dense foods and reduced physical activity, leading to dysfunction of major tissues and organs and alarming increases in the incidence of obesityrelated diseases such as diabetes, hypertension, and cardiovascular disease. Skeletal muscle has received particular attention, because it is the major site of glucose disposal, accounting for approx 80% of glucose clearance in the postprandial state.
With the recent advent and integration of tools of molecular biology and comprehensive metabolic analysis, a review of mechanisms by which overconsumption of energy rich diets leads to insulin resistance in skeletal muscle seems warranted. Particular themes that will be highlighted in this chapter include:
1) Inter-organ communication networks among liver, adipose tissue, and muscle that contribute to muscle insulin resistance;
2) Critical evaluation of the idea that lipid-induced muscle insulin resistance occurs as a consequence of reduced fatty acid oxidation, leading to accumulation of toxic lipid-derived metabolites and TAG; 3) Discussion of an alternative and recently emergent concept that accumulation of lipid-derived metabolites that interfere with insulin action occurs due to an increase rather than a decrease in fatty acid oxidation in skeletal muscle.
