Downregulation of genes involved in NFκB activation in peripheral blood mononuclear cells after weight loss is associated with the improvement of insulin sensitivity in individuals with the metabolic syndrome: the GENOBIN study

Abstract

Aims/hypothesis The transcription factor nuclear factor-kappa-B (NFκB) is implicated in inflammatory responses, obesity and the metabolic syndrome, while immune cells appear to play a central role in mediating insulin resistance and can be used as a model to study inflammation and its relationship with insulin resistance. In peripheral blood mononuclear cells of overweight participants with the metabolic syndrome, we evaluated (1) the effect of diet-induced weight loss on the expression of genes involved in NFκB activation and (2) their association with insulin sensitivity. The genes studied were: TNF receptors TNFRSF1A and TNFRSF1B, and IL1R1, TLR4, TLR2, ICAM1, CCL5 and IKBKB. Methods We analysed data from 34 overweight participants with abnormal glucose metabolism and the metabolic syndrome, who were randomised to a weight-reduction (n=24) or control group (n=10) for 33 weeks. The mRNA expression was measured using real-time PCR. Measures of insulin and glucose homeostasis were assessed by IVGTT and OGTT. Results In general, the genes studied were downregulated after weight loss intervention. The changes in TLR4, TLR2, CCL5 and TNFRSF1A mRNA expression were associated with an increase in insulin sensitivity index independently of the change in waist circumference (p<0.05). The change in IKBKB expression correlated with most of the changes in gene expression in the weight-reduction group. Conclusions/interpretation These results suggest that proteins encoded by CCL5, TLR2 and TLR4, and TNFRSF1A might contribute to insulin-resistant states that characterise obesity and the metabolic syndrome.

Peripheral mononuclear blood cells contribute to the obesity-associated inflammatory state independently of glycemic status: involvement of the novel proinflammatory adipokines chemerin, chitinase-3-like protein 1, lipocalin-2 and osteopontin

“…Reportedly, T2D obese patients exhibit higher expression levels of TNF receptor (TNFR)-2 in PBMC compared to normoglycemic obese individuals (Fogeda et al 2004). Moreover, diet-induced weight loss in individuals with metabolic syndrome altered the gene expression of cytokines related to inflammation (de Mello et al 2008b) and also resulted in a decreased expression of genes involved in the activation of the transcription factor nuclear factor j B (NFjB) in PBMC (de Mello et al 2008a). In addition, an association between white blood cell subtypes and measures of insulin resistance has been recently described (Lee et al 2014).…”

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

“…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).…”

“…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). On the other hand, it has been shown that insulin suppresses TLR expressions (21) and NF-kB binding activity (22) in PBMCs.…”

“…study the relationship between low-grade inflammation and insulin resistance (10,11,22,23,24). As such studies have never been carried out in patients with gestational diabetes (GDM), we hypothesized that the development of insulin resistance and hyperglycemia during pregnancy may influence the expression of genes encoding receptors of surface ligands and immune mediators involved in NF-kB signaling pathway.…”

Transcriptomic profiles of skeletal muscle tissue following an euglycemic-hyperinsulinemic clamp in insulin-resistant obese subjects

“…Secondly, a chronic systemic low-grade inflammation is typically observed in obese subjects. The beneficial effect of weight loss was associated with the modification of the inflammation-related gene expression (Clement et al 2004;de Mello et al 2008). Further, gene expression in obese subjects after dietary restriction was closer to the profile of lean subjects than to the pattern of obese subjects before dietary restriction (Clement et al 2004).…”