Does a high fat diet induce skeletal muscle insulin resistance due to increased endoplasmic reticulum stress?

The endoplasmic reticulum (ER) is an organelle found in most eukaryotic cells, including skeletal muscle, and serves multiple functions related to the synthesis, folding, and transport of proteins. Accumulating evidences suggests that ER stress affects protein folding, increases cellular inflammation and has a role in the pathogenesis of diabetes (4, 73). When the ER is stressed due to hyperglycemia and hyperlipidemia, the unfolded protein response (UPR) is activated in attempt to restore ER homeostasis (4). Failure to restore ER homeostasis may lead to unresolvable UPR activation and β-cell death, which is a telltale sign of type 2 diabetes (28). It is well documented that the high fat-fed Sprague Dawley rat exhibits increased levels of circulating lipid intermediates, resulting in elevated inflammatory activity, lipodystrophy, obesity, and insulin resistance (30, 65). IKK inflammatory pathway activity is elevated in the skeletal muscle of high fat-fed Sprague Dawley rats, which may contribute to skeletal muscle insulin resistance (49, 96). Additionally, increased IKK inflammatory pathway activity occurs in response to lipid intermediates and TNF-α in adipose (30), hepatic (9, 67), and cardiac tissue resulting in ER stress (14, 27). It is unknown as to what governs elevated IKK inflammatory activity in skeletal muscle, but a mediator must exist to link increased lipid intermediate concentrations and IKK pathway activity in response to the skeletal muscle of the high fat-fed rat. ER stress has been suggested to be responsible for the increased activation of the IKK inflammatory pathway in hepatic (5, 17, 36, 60, 94), cardiac (3, 34, 37, 43, 74), and adipose tissue (11, 20, 45, 55), but it uncertain if similar effects are found in insulin resistant skeletal muscle tissue. It is possible that ER stress is the link between elevated lipid intermediates in skeletal muscle and increased IKK inflammatory pathway activity.