TNF-α can certainly produce local and downstream endothelial activation and inhibition of NO production in small vessels. In rats, TNF-α elevation concomitantly impairs insulin-mediated muscle capillary

recruitment and glucose uptake [124]. Moreover, in isolated skeletal muscle resistance arteries, TNF-α impairs the vasodilator effects, but not the vasoconstrictor effects of insulin through activation of intracellular Selleck Selumetinib enzyme JNK and impairment of insulin-mediated activation of Akt (Figure 3) [30]. This selective inhibition of the vasodilator effects of insulin results in insulin-mediated vasoconstriction in the presence of TNF-α. JNK has been shown to regulate whole-body insulin sensitivity as well as insulin-mediated cell signaling [40]. In cultured bovine aortic endothelial cells, TNF-α induces insulin resistance in the PI3K/Akt/eNOS pathway and enhances ERK1/2 and AMPK phosphorylation [72]. In humans, the TNF-α gene locus contributes to

the determination of obesity and obesity-associated hypertension [89]. Recent interesting evidence is that insulin sensitivity is improved by treatment through neutralizing TNF-α with the monoclonal antibody, infliximab, in patients with ankylosing spondylitis [63], indicating that TNF-α is indeed an important adipokine that may be at least partially responsible for an insulin-resistant state. Notably, compared with healthy controls, patients with ankylosing spondylitis had impaired microvascular endothelium-dependent vasodilatation and capillary recruitment, Akt inhibitor which was normalized following anti-TNF-α treatment [110]. Morphological studies reveal substantial differences in inflammation between subcutaneous and intra-abdominal (visceral) fat depots. Dimethyl sulfoxide Abdominal adipose tissue contains more monocytes and macrophages, and expresses more TNF-α than subcutaneous adipose tissue in obesity [8,42]. In accordance, increased visceral adipose tissue

and trunk/extremity skinfold ratio were shown to be associated with an increased inflammation score, which combined information on concentrations of C-reactive protein, IL-6, and TNF-α. However, levels of circulating TNF-α are associated with capillary recruitment in some [45], but not in all studies [20]. This may be explained by the fact that TNF-α may not be a good candidate as a systemic fat-derived signal, due to its low circulating concentration [41]. A new source of TNF-α, which has recently been identified, is perivascular adipose tissue around coronary arteries [13,81]. This implies that TNF-α is produced in the vicinity of the vascular endothelium, and may mean that circulating levels of TNF-α underestimate the biologically relevant concentrations of this cytokine.