Endothelial Metabolic Inflammation: A Link between High Fat Feeding,Insulin Resistance, and Impaired Trans-Endothelial Insulin Transport

Copyright: © 2012 Wang H. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Obesity and its associated metabolic syndrome and type 2 diabetes are becoming epidemics in the United States. The most recent data show that nationwide incidence of obesity (BMI > 30 kg/ m) and type 2 diabetes has reached to 27.8% and 8.7%, respectively (CDC Behavioral Risk Factor Surveillance System 2012). Endothelial dysfunction, characterized by a deficiency of bio-available nitric oxide (NO), has been found to precede the development of type 2 diabetes and is significantly correlated with insulin resistance [1]. Early studies have shown that feeding rodent animals with a high fat diet (HFD) (~60% of calories) produces not only obesity [2] but also a state of insulin resistance [3]. These HFD-fed rodents develop striking hyperinsulinemia with significantly reduced whole body insulin sensitivity and glucose disposal rates, severe impairments in both muscle and adipose tissue insulin signaling and glucose uptake and an impairment of insulin-mediated suppression of hepatic glucose output [4-6]. Moreover, obesity has been shown to be a state of low-grade chronic systemic inflammation known as the metabolic inflammation characterized by elevated levels of pro-inflammatory cytokines (such as TNFα, IL-6, IL-1β, CCL2 etc.), accumulation of leukocytes within adipose tissue and other organs, activation of macrophages in both liver and fat and activation of pro-inflammatory signaling pathways in multiple organs or tissues [7,8]. The mechanisms causing the metabolic inflammation have been related to excess nutrient intake (metabolic stress) including HFD feeding [7,8]. Dietary fat intake not only significantly increases circulating free fatty acids (FFAs) concentration but also affects the composition of circulating FFAs [9]. Four-week HFD feeding has been shown to cause metabolic endotoxemia leading to the metabolic inflammation in mice [10]. The lipopolysaccharide (LPS) -induced inflammatory responses in macrophages have been shown to be mediated by Toll-Like Receptor-4 (TLR4) (pattern recognition receptors that sense lipopeptides and lipopolysaccharides of bacterial walls) [11]. Interestingly, saturated fatty acids (SFAs), but not unsaturated fatty acids, can induce an inflammatory response like LPS through activation of TLR4 [12,13]. It has also been proposed that nutrients per se are naturally inflammatory [7]. While the flood of nutrients in a short period of time may induce a brief episode of stress signaling in the target cells, long-chain SFAs, particularly palmitate, have been shown to directly activate TLR4 that may require CD36 (a class B scavenger receptor) [14-16], leading to IKKβ/NFκB and c-jun N-terminal kinase (JNK) pathway activation, increased production of pro-inflammatory cytokines TNFα, IL-1β and IL-6 [13,17-19] and significant insulin resistance as reflected by impairments in insulinstimulated tyrosine phosphorylation of IRS-1, serine phosphorylation of Akt and eNOS, and NO production. Interestingly, recent studies have shown evidence that vascular endothelium that line up the inner wall of vasculature appear to be the first responder to the environmental insult, high fat feeding, leading to the vascular endothelial metabolic inflammation and insulin resistance.