Comment on Boden et al. Insulin Regulates the Unfolded Protein Response in Human Adipose Tissue. Diabetes 2014;63:912–922

Abstract

Boden et al. (1) reported that insulin-induced endoplasmic reticulum (ER) stress increased in subcutaneous adipose tissue of human subjects in vivo. The authors elegantly show that the induction of the unfolded protein response was not related to increased glucose metabolism or oxidative stress. The response was, however, associated with accumulation of ubiquitination-associated proteins, some of which are potential causes for ER stress. From these data, the authors conclude that they revealed a putative mechanism for the development of ER stress in obesity. Whether or not the activating effect of insulin on ER stress will become resistant in the setting of obesity-associated insulin resistance was not addressed.We have previously shown insulin-induced markers of ER stress in primary mouse hepatocytes. The effect was completely prevented by the inhibition of phosphatidylinositide 3 (PI3) kinase (2). Therefore, we addressed the question of whether or not the activating effect of insulin on ER stress is abrogated in the setting of insulin resistance. Mice were studied in vivo after a 3-day high-fat diet, a dietary challenge that results in hepatic lipid accumulation and hepatic insulin resistance (3-5). In this setting, insulin still increased hepatic Grp78 protein expression as well as X-box binding protein 1 (XBP1s) and C/EBP homologous protein (CHOP) mRNA expression, while other functions of insulin, such as suppression of hepatic glucose output, were decreased (2,6). Moreover, in mice functionally lacking the eIF2a-mediated branch of the unfolded protein response (7), the increase in XBP1s and CHOP by insulin was further enhanced, demonstrating that the eIF2a-mediated arm of the unfolded protein response is needed to properly resolve insulinmediated ER stress (2,8). It would be important to understand whether or not insulin-resistant humans also remain sensitive to insulin-induced ER stress.