The role of gut microbiota on insulin resistance

Andrea M Caricilli, Mario J A Saad, Andrea M Caricilli, Mario J A Saad

Abstract

The development of obesity and insulin resistance has been extensively studied in the last decades, but the mechanisms underlying these alterations are still not completely understood. The gut microbiota has been identified as a potential contributor to metabolic diseases. It has been shown that obese individuals present different proportions of bacterial phyla compared with lean individuals, with an increase in Firmicutes and Actinobacteria and a decrease in Bacteroidetes. This alteration seems to interfere with intestinal permeability, increasing the absorption of lipopolysaccharide (LPS), which reaches circulation and initiates activation of Toll-like receptor (TLR) 4 and 2 and LPS receptor CD14, leading to increased activation of inflammatory pathways. With these activations, an impairment of the insulin signaling is observed, with decreased phosphorylation of the insulin receptor, insulin receptor substrate (IRS) and Akt, as well as increased inhibitory serine phosphorylation of IRS-1. Altered proportions of bacterial phyla have also been demonstrated to interfere with host's biochemical pathways, increasing energy extraction and depot in adipose tissue. Therefore, understanding the mechanisms by which the alteration in the gut microbiota produces different signaling activations and phenotype changes may offer an interesting opportunity for the treatment of obesity and type 2 diabetes.

Figures

Figure 1
Figure 1
Alteration in gut microbiota composition due to obesity is accompanied by changes in activation of enzymes and pathways, leading to and increased inflammatory state and energy harvest. AMPK: AMP-activated kinase; SCFA: short-chain fatty acids; LPL: lipoprotein lipase; ACC: acetyl-CoA carboxylase; CPT1: carnitine palmitoyltransferase I.
Figure 2
Figure 2
Insulin signaling is affected by Toll-like Receptor (TLR)2 and 4 signaling. LPS: lipopolysaccharide; IRS: insulin receptor substrate; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; IKK: IκB kinase; JNK: c-Jun N-terminal kinase; MyD88: Myeloid differentiation primary gene response (88); MAL/TIRAP: MyD88 adapter-like; TRAF6: TNFR-associated factor 6; IRAK: interleukin-1 receptor-associated kinase; TAK1: Transforming Growth Factor β-activated kinase 1.
Figure 3
Figure 3
Metabolic endotoxemia leads to activation of insulin resistance in muscle, liver, adipose tissue and hypothalamus through activation of Toll-like receptor (TLR)2 and 4. JNK: c-Jun N-terminal kinase; IKK: IκB kinase; LPS: lipopolysaccharide; MD-2: myeloid differentiation factor-2.
Figure 4
Figure 4
Alteration of intestinal permeability after change in gut microbiota of obese individuals. LPS: lipopolysaccharide; TLR: Toll-like Receptor; ZO-1: zonula occludens.

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