microRNA-205-5p is a modulator of insulin sensitivity that inhibits FOXO function

Fanny Langlet, Marcel Tarbier, Rebecca A. Haeusler, Stefania Camastra, Eleuterio Ferrannini, Marc R. Friedländer, Domenico Accili

miRNAs regulate gene expression in physiologic and disease conditions, including type 2 diabetes (T2D). Genome-wide association studies for T2D susceptibility loci indicate that most of the diabetes-associated variants localize to noncoding regions, raising the possibility that miRNAs transcribed from these regions contribute to disease development. Given the role of the transcription factor Forkhead Box Protein O (FOXO) in insulin action, Langlet et al. undertook a systematic search for FOXO-regulated hepatic miRNAs and identified miR-205-5p as an endogenous regulator of insulin sensitivity that coordinately targets components of the insulin signaling cascade, including FOXO itself.

Objective: Hepatic insulin resistance is a hallmark of type 2 diabetes and obesity. Insulin receptor signaling through AKT and FOXO has important metabolic effects that have traditionally been ascribed to regulation of gene expression. However, whether all the metabolic effects of FOXO arise from its regulation of protein-encoding mRNAs is unknown.

Methods: To address this question, we obtained expression profiles of FOXO-regulated murine hepatic microRNAs (miRNAs) during fasting and refeeding using mice lacking Foxo1, 3a, and 4 in liver (L-Foxo1,3a, 4).

Results: Out of 439 miRNA analyzed, 175 were differentially expressed in Foxo knockouts. Their functions were associated with insulin, Wnt, Mapk signaling, and aging. Among them, we report a striking increase of miR-205-5p expression in L-Foxo1,3a,4 knockouts, as well as in obese mice. We show that miR-205-5p gain-of-function increases AKT phosphorylation and decreases SHIP2 in primary hepatocytes, resulting in FOXO inhibition. This results in decreased hepatocyte glucose production. Consistent with these observations, miR-205-5p gain-of-function in mice lowered glucose levels and improved pyruvate tolerance.

Conclusions: These findings reveal a homeostatic miRNA loop regulating insulin signaling, with potential implications for in vivo glucose metabolism.