Role of miR-383 and miR-146b in different propensities to obesity in male mice

The study was designed to investigate the possible mechanisms of hepatic microRNAs (miRs) in regulating local thyroid hormone (TH) action and ultimately different propensities to high-fat diet (HFD) induced obesity. When obesity-prone (OP) and obesity-resistant (OR) mice were fed high-fat diet for 7 weeks, OP mice showed apparent hepatic steatosis, with significantly higher body weight and lower hepatic thyroid hormone receptor b (TRb) expression and type 1 deiodinase (DIO1) activity than OR mice. Next-generation sequencing technology revealed that 13 miRs in liver were dysregulated between the two phenotypes, of which 8 miRs were predicted to target on Dio1 or TRb. When mice were fed for 17 weeks, OR mice had mild hepatic steatosis and increased Dio1 and TRb expression than OP mice, with down-regulation of T3 target genes (including Srebp1c, Acc1, Scd1, Fasn) and up-regulation of Cpt1α, Atp5c1, Cox7c, and Cyp7a1. A stem-loop qRT-PCR analysis confirmed the levels of miR-383, miR-34a and miR-146b were inversely correlated with DIO1 or TRb. Inhibition of miR-383 or miR-146b expression by way of their inhibitors in primary mouse hepatocytes upon free fatty acid treatment led to increased DIO1 and TRb, respectively, and subsequently decreased cellular lipid accumulation, while miR-34a inhibitor transfection had on effects on TRb expression. Luciferase reporter assay illustrated that miR-146b could directly target TRb 3'untranslated region (3'UTR). These findings suggested that miR-383 and miR-146b might play a critical role in different propensities to diet-induced obesity via targeting on DIO1 and TRb, respectively.

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