Efeito de um inibidor do TLR4 na sensibilidade e sinalização de insulina em camundongos obesos / Effect of TLR4 pharmacologic inhibitors in the insulin signalization and sensitivity in obese animals

AUTOR(ES)

Nilton Sergio de Aquino

DATA DE PUBLICAÇÃO

2009

RESUMO

Insulin resistance and type 2 diabetes are associated with obesity and a state of abnormal inflammatory response. TLR4 detects Gram-negative bacteria through recognition of the lipid A moiety of lipopolysaccharide (LPS) and has an important role in inflammation and immunity. Since it is activated by LPS and saturated fatty acids, which are inducers of insulin resistance, TLR4 appears as a candidate for participation in the cross-talk between inflammatory and metabolic signals. We investigated, herein, in vivo efficacy and associated molecular mechanisms by TAK 242, a small-molecule selective TLR4 inhibitor, improved diabetes control and insulin action. The effect of TAK 242 was investigated on insulin sensitivity, insulin signaling and activity in tissues of high-fat dietfed mice. Moreover, these mice showed significantly improved insulin sensitivity, improved glucose tolerance and enhanced insulin signaling capacity in adipose tissue, muscle and liver as compared to control mice during high fat feeding. TAK 242, in our endotoxin shock model, by oral administration, also demonstrated efficacy against the LPSinduced cytokines with a high survival rate and improved insulin sensibility in mice. In conclusion, we demonstrated that TAK-242, a small-molecule selectively suppresses TLR4-signaling, improves glucose tolerance and insulin action in high-fat dietfed mice. Manipulation of TLR4 pathways is considered to have great therapeutic potential. Cyclohexene derivatives, like TAK-242, represent a novel therapeutic approach to the treatment of human obesity, insulin resistance and type 2 diabetes.

ASSUNTO(S)

diabetes mellitus tipo 2 receptor 4 toll-like toll-like receptor 4 type 2 insulin resistance diabetes mellitus resistência à insulina

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