Mice with Fas deficiency either in all cells or specifically in adipocytes (the latter are referred to herein as AFasKO mice) were protected from deterioration of glucose homeostasis induced by high-fat diet (HFD). Adipocytes in AFasKO mice were more insulin sensitive than those in wild-type mice, and mRNA levels of proinflammatory factors were reduced in white adipose tissue. Moreover, AFasKO mice were protected against

hepatic steatosis and were more insulin sensitive, both at the whole-body level and in the liver. Thus, Fas in adipocytes contributes to adipose tissue inflammation, hepatic steatosis, and insulin resistance induced by obesity and may constitute CAL-101 cost a potential therapeutic target for the treatment of insulin resistance and type 2 diabetes. © 2010 American Society for Clinical Investigation. The

cluster of clinical features comprising visceral adiposity, insulin resistance (IR) and glucose intolerance, atherogenic dyslipidemia, and hypertension, which combined are operationally defined RO4929097 cell line as the metabolic syndrome (MetS), is increasing in incidence and prevalence at alarming rates in both developed and developing nations. The primary driver of this trend is the net positive energy balance resulting from overconsumption of food and our associated sedentary lifestyle, leading to increased weight and ultimately obesity. A large body of literature has now established that obesity is associated with a low-grade selleck chemicals llc systemic inflammatory response that contributes to IR and type 2 diabetes.1 The cells and tissue types involved in this response are not fully understood, but evidence points to adipocytes because they are first affected by the increased metabolic load and the associated immune cells which infiltrate adipose tissues in obesity. Consistent with this notion, altered regulation of inflammatory stress-response genes

and adipokines such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), leptin, adiponectin IL-receptor α, and IL-8 has been demonstrated in the adipose tissues of obese animals.2 With this change is an increase in the number and activation status of adipose-infiltrating macrophages resulting in further production of inflammatory factors,3-5 which inhibits the activity of the insulin receptor signaling pathway, leading to IR. Intimately linked to the MetS and visceral obesity is hepatic steatosis, characterized by the build-up of intrahepatic triglyceride.6 Recent studies suggest that intrahepatic triglyceride is a better marker of the progressive impairment of insulin action on the liver and in peripheral tissues, including skeletal muscle and adipose tissue.7, 8 The mechanisms responsible for hepatic IR are not known.