Fat Partitioning and Insulin Sensitivity

Abstract

The evidence is now compelling that an excess supply of fatty acids, beyond that required for energy needs, is a cause of muscle insulin resistance. Intramyocellular triglyceride accumulation is a marker of excess fatty acid supply to muscle, and it is now two decades since an association was recognized between intramyocellular triglyceride accumulation and insulin resistance (1). Arguably, the major issues now (2,3) are to first pin down the causal mechanisms between fatty acid oversupply and insulin resistance (the prevailing view is that triglycerides themselves do not cause insulin resistance because they localize within discrete lipid droplets), second, define and develop appropriate therapeutic strategies, and third, clarify the place of dysregulated lipid metabolism against other, not necessarily mutually exclusive, putative causes of insulin resistance (4). In this issue of Diabetes , Wang et al. (5) have generated a novel skeletal muscle–specific lipoprotein lipase knockout−/−mouse line (SMLPL−/−) to better understand how lipid-derived signals integrate with insulin signaling and how reducing skeletal muscle lipoprotein lipase affects systemic fatty acid partitioning and insulin sensitivity. The studies clearly support the view that partitioning fat away from skeletal muscle reduces muscle triglyceride content and improves insulin sensitivity. This result is hardly surprising given the plethora of genetic and nutritional evidence showing that manipulation of fatty acid supply to muscle produces reciprocal changes in insulin sensitivity (2,3). For example, mice with genetically enhanced muscle lipoprotein lipase expression exhibit insulin resistance (6). However, …