Figure 1. Fatty acid metabolism and insulin action in skeletal muscle or liver.

Obesity results in an increased flux of free fatty acids into the circulation and uptake by the myocyte or hepatocyte. Activated fatty acids (i.e., fatty acyl-CoAs) are “metabolized” primarily via one of two pathways, oxidation or storage. When fatty acid flux exceeds the ability of these pathways to dispose of fatty acyl-CoAs, intermediaries of fatty acid metabolism (e.g., DAG, PA, LPA, ceramide) accumulate. In turn, these fatty acid intermediates can activate a number of different serine kinases that can negatively regulate insulin action. Ceramide can also impair insulin action through interactions with PKB/Akt. An inability to completely oxidize fatty acids through β-oxidation, which leads to an accumulation of acylcarnitines, has also been hypothesized to cause insulin resistance, although the precise mechanisms leading to insulin resistance are, to date, unknown. AGPAT, acylglycerol-3-phosphate acyltransferase; PAP, PA phosphohydrolase.