Storing up trouble: does accumulation of intramyocellular triglyceride protect skeletal muscle from insulin resistance?

1. Insulin resistance occurs when normal amounts of insulin are inadequate to produce a normal insulin response from cells. This is important in the context of whole-body glucose homeostasis because skeletal muscle is the main tissue for insulin-stimulated glucose disposal. 2. In obesity, lipid deposition in peripheral tissues, such as skeletal muscle, is linked to the activation of stress kinases and the development of insulin resistance. Accumulation of intramyocellular triglyceride (IMTG) is positively associated with insulin resistance; however, it is unknown whether IMTG causes insulin resistance or protects cells from insulin resistance by preventing the accrual of bioactive lipid metabolites. 3. The role of IMTG in the development of insulin resistance is not resolved. Stable overexpression of the triglyceride lipase adipose triglyceride lipase (ATGL) reduced IMTG content in myotubes, but resulted in a concomitant increase in diacylglycerol (DAG) and ceramide and caused insulin resistance. Increasing TG content by muscle-specific overexpression of diacylglycerol acyltransferase (DGAT) 1 protected mice from insulin resistance. Conversely, overexpression of DGAT2 in glycolytic muscle resulted in accumulation of TG and ceramide and insulin resistance in these tissues. This was sufficient to induce whole-body insulin and glucose insensitivity. 4. It is unlikely that IMTG causes cause insulin resistance directly. Instead, it appears as though TG accumulates in skeletal muscle to sequester fatty acids and to protect from the deleterious actions of lipids, such as ceramide and DAG. Whether lipase inhibitors are viable therapeutics to prevent obesity induced insulin resistance is unknown, but future studies examining tissue-specific ATGL/hormone-sensitive lipase knockouts will hopefully resolve this question.