microRNA-205-5p is a modulator of insulin sensitivity that inhibits FOXO function
| Autor: | Fanny Langlet, Eleuterio Ferrannini, Marcel Tarbier, Rebecca A. Haeusler, Domenico Accili, Stefania Camastra, Marc R. Friedländer |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male medicine.medical_treatment Genetics Glucose production Insulin resistance Liver metabolism Transcriptional regulation Type 2 diabetes Mice Obese FOXO1 Mice Insulin Regulation of gene expression Mice Knockout biology Molecular Biology Cell Biology Wnt signaling pathway Forkhead Transcription Factors Middle Aged Cell biology Liver Female Original Article hormones hormone substitutes and hormone antagonists Signal Transduction Adult lcsh:Internal medicine Diet High-Fat 03 medical and health sciences microRNA medicine Animals Humans lcsh:RC31-1245 Protein kinase B medicine.disease Mice Inbred C57BL Insulin receptor MicroRNAs 030104 developmental biology Glucose Diabetes Mellitus Type 2 biology.protein Hepatocytes Proto-Oncogene Proteins c-akt |
| Zdroj: | Molecular Metabolism Molecular Metabolism, Vol 17, Iss, Pp 49-60 (2018) Molecular Metabolism, vol. 17, pp. 49-60 |
| Popis: | Objectives 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. Highlights • A comprehensive analysis of Foxo-dependent miRNA. • miRNAs recapitulate the transcriptional effects of Foxo on insulin signaling. • Foxo regulates miRNA transcription during the fasting/refeeding transition. • miR205 regulates insulin sensitivity through a homeostatic loop with Foxo. |
| Databáze: | OpenAIRE |
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