Identificación y caracterización funcional de microARNs desregulados por acción del TNFα en el contexto de la Obesidad y la Resistencia a la Insulina

Identifier:  TDX:2817

Handle: https://hdl.handle.net/20.500.11797/TDX2817

Authors:  Lozano Bartolomé, Javier

Abstract:
The proinflammatory cytokine TNFα is a key player in insulin resistance (IR). While several miRNAs are believed to be involved in the development of adipose tissue (AT) IR, the role of miRNAs in the association between inflammation and IR is poorly understood. The aim of the present study is to analyse the expression profile of selected 25 miRNAS in obesity, and to investigate their role in TNFα-induced IR in adipocytes. For this we employed three cohorts. Cohort 1 for AT expression studies and included 28 subjects with BMI<30 and 30 subjects with BMI≥30. For circulating serum studies we used: Cohort 2 that included 101 subjects with 4-years follow-up (48 incident pre-diabetes and 53 controls) and Cohort 3 that included 100 subjects (50 diabetic and 50 controls). Functional analysis was performed in human adipocytes using miRNA mimics and inhibitors. Key molecules of the insulin pathway, AKT, AS160, PTEN and S6K, were analyzed. Our results showed that from the selected panel of miRNAs, only miR-181a-5p and miR-23a-3p were markedly altered in human IR adipocytes. Expression of miR-181a-5p and miR-23a-3p was reduced in AT from obese and diabetic subjects and was inversely related to adiposity and IR. Overexpression of miR-181a-5p and miR-23a-3p in adipocytes, upregulated insulin-stimulated AKT activation and, reduced TNFα-induced IR through modulation of PTEN and S6K expression. Circulating levels of miR-181a-5p and miR-23a-3p in serum did not change in diabetic patients respect to healthy donors, while circulating levels of miR-181a-5p in prediabetic subjects at baseline were reduced when compared to controls. Variable importance in projection scores revealed miR-181a-5p had more impact in the model than insulin or glucose at 120 minutes. Overall we can conclude that miR-181a-5p and miR-23a-3p have a potential regulatory role in obesity-related TNFα-associated IR in adipocytes. We also show that miR-181a-5p is deregulated before the onset of prediabetes.