Inflammation and atherosclerosis: role of adipokines

Abstract

Both atherosclerosis and obesity, an independent atherosclerotic risk factor, are associated with enhanced systemic inflammation. Recent studies suggest that adipose tissue inflammation in the obese individual, leading to dysregulation of adipocyte secretion, may play a causative role in obesity related atherosclerosis. In ApoE-/- mice crossbred with transgenic mice with adipose-specific expression of a dominant negative form of c-Jun N-terminal kinase (JNK), the selective suppression of fat inflammation could protect against the development of atherosclerosis, despite a high fat high cholesterol diet. This protection against atherosclerosis was mediated through the attenuation of visceral fat and systemic inflammation, without changes in lipid or glucose metabolism. Lean apoE-/- mice that received transplantation of visceral fat from obese wild-type donor mice for 4 weeks showed exacerbated systemic inflammation and atherosclerotic plaque formation. Conversely, apoE-/- recipients carrying visceral fat graft from obese mice with adipose-specific JNK inactivation were protected against enhanced systemic inflammation and atherogenesis. The beneficial effects of adipose-specific JNK inactivation on atherogenesis in apoE-/- recipients were significantly compromised by continuous infusion of recombinant adipocyte fatty acid binding protein (A-FABP), previously shown to interact with JNK via a positive feedback loop to modulate inflammatory responses. These data suggest that enhanced atherosclerosis in obesity can be attributed, at least in part, to a distant cross-talk between visceral fat and the vasculature, mediated by the release of pro-inflammatory adpokines, such as A-FABP, from the inflamed visceral adipose tissue. In humans, high circulating A-FABP levels predicted cardiovascular diseases and, as a biomarker for the prediction of coronary events in patients with established coronary artery disease, appeared to be superior to other adipokines. Taken together, these findings imply that life-style and pharmacological measures which reduce A-FABP expression in visceral adipose tissue may have potential therapeutic benefit in the prevention and treatment of atherosclerotic diseases.