Endoplasmic Reticulum Stress: Another Link Between Obesity and Insulin Resistance/Inflammation?

Abstract

Obesity, which has reached epidemic proportions in the U.S. and is increasing worldwide, is closely associated with insulin resistance (peripheral and hepatic) and with a state of low-grade inflammation, the latter characterized by elevated levels of proinflammatory cytokines in blood and tissues (1). Insulin resistance and inflammation in turn are associated with type 2 diabetes, hypertension, atherogenic dyslipidemias, and disorders of blood coagulation and fibrinolysis, all of which are independent risk factors for the development of atherosclerotic vascular disease, including heart attacks, strokes, and peripheral arterial disease (1). The reason why obesity is so closely associated with insulin resistance and inflammation is not completely understood. On one hand, there is evidence to show that blood levels of free fatty acids (FFAs) play an important role in the development of obesity-related insulin resistance and inflammation (rev. in 2). Plasma FFA levels are increased in most obese people, and acutely raising plasma FFA levels increases insulin resistance as well as the expression of proinflammatory cytokines, whereas lowering plasma FFA levels reduces insulin resistance. Mechanisms involved in FFA-induced insulin resistance include accumulation (in muscle and liver) of lipids and lipid intermediates such as diacylglycerol, activation of several protein kinase C isoforms, reduction in tyrosine phosphorylation of the insulin receptor substrates 1 and 2 (2), and activation of the proinflammatory nuclear factor-κB pathway (3,4). On the other hand, not all obese insulin-resistant subjects have elevated plasma …