Increased Toll-Like Receptor Activity in Patients With Metabolic Syndrome

Abstract

OBJECTIVEThe metabolic syndrome (MetS) is highly prevalent and confers an increased risk for diabetes and cardiovascular disease (CVD). While MetS is a proinflammatory state, there is a paucity of data on cellular inflammation in MetS. Toll-like receptors (TLRs) are classical pattern recognition receptors of the innate immune response.RESEARCH DESIGN AND METHODSThe aim of this study was to examine monocyte TLR2 and TLR4 in MetS patients without diabetes or CVD and control subjects since both of the receptors have been implicated in atherosclerosis and insulin resistance. Fasting blood was obtained for TLR expression and activity.RESULTSCirculating levels of high-sensitivity C-reactive protein, interleukin (IL)-1β, IL-6, IL-8, and soluble tumor necrosis factor receptor 1 (sTNFR1) were significantly increased in MetS versus control subjects following adjustment for waist circumference. There was a significant increase in both TLR2 and TLR4 surface expression and mRNA on monocytes after adjustment for waist circumference. In addition to increased nuclear factor-κB nuclear binding, there was significantly increased release of IL-1β, IL-6, and IL-8 in MetS versus control subjects following priming of the monocytes with lipopolysaccharides. While both plasma free fatty acids and endotoxin were increased in MetS, they correlated significantly with TLR4 only.CONCLUSIONSIn conclusion, we make the novel observation that both TLR2 and TLR4 expression and activity are increased in the monocytes of patients with MetS and could contribute to increased risk for diabetes and CVD.

The expression of genes involved in NF-κB activation in peripheral blood mononuclear cells of patients with gestational diabetes

“…suppressive, effect on TLR expressions in PBMCs (21) so that insulin deficit or insulin resistance would be expected to result in TLR expression upregulation. Indeed, TLR2 and TLR4 expressions have been shown to be increased in the skeletal muscle and adipose tissue of type 2 diabetic subjects (12,19), as well as in the monocytes obtained from the patients with both type 1 (36) and type 2 diabetes (14), and the metabolic syndrome (15).…”

“…In addition to host defense against foreign pathogens, recent studies implicate a role of NF-kB (7,8,9,10,11) and TLR pathway (10,12,13,14,15,16,17,18,19,20) in the pathogenesis of obesity-and type 2 diabetesrelated insulin resistance and metabolic disturbances. Moreover, de Mello et al (10,11) demonstrated that in patients with the metabolic syndrome, the changes in insulin resistance were associated with the changes in the expression of genes involved in the NF-kB signaling pathways in peripheral blood mononuclear cells (PBMCs).…”

4-Hydroxyisoleucine from Fenugreek (Trigonella foenum-graecum): Effects on Insulin Resistance Associated with Obesity

“…The natural ligand for TLR4 is lipopolysaccharide, the Gram-negative bacterial wall component that is structurally similar to FFAs [25]. Indeed, obese individuals show upregulation of TLR4 in cells and tissues (including monocytes), adipose tissue, and skeletal muscle [27,28]. Therefore, a diet high in saturated FFAs can activate TLR4, leading to JNK activation, which in turn activates nuclear factor (NF)-κB [25,29].…”

Plasma fetuin-A does not correlate with monocyte TLR4 in humans

“…Hence, in a preliminary analysis of the patients with the metabolic syndrome included in our study, in whom we had previously shown increased monocyte TLR4 activity that correlated with insulin resistance, NEFA and endotoxin levels [5], we assayed fetuin-A in remaining frozen plasma samples. All participants gave informed consent to participate in the original study and the protocol was approved by the UC Davis Institutional Review Board.…”