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

Molecular Metabolism
Fanny LangletDomenico Accili

Abstract

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. 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). 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. These findings reveal a homeostatic miRNA loop regulating insulin signaling, with potential implic...Continue Reading

Citations

Jun 19, 2019·International Journal of Molecular Sciences·Francesca CirilloMaria Elisabeth Street
Aug 14, 2019·Hepatology Research : the Official Journal of the Japan Society of Hepatology·Mette Yde HochreuterRomain Barrès
Nov 26, 2019·Aging Cell·Yan HuangXiang-Hang Luo
Nov 25, 2018·International Journal of Molecular Sciences·Laura NigiGuido Sebastiani
Jul 4, 2020·Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico·J PengR Zeng
Apr 5, 2020·Cells·Laura IoannilliMaria Rosa Ciriolo
Jul 19, 2019·Cell Communication and Signaling : CCS·Yinfang WangPeng Zhang
Sep 24, 2020·International Journal of Molecular Sciences·Adam WłodarskiAgnieszka Śliwińska
Aug 25, 2019·Trends in Endocrinology and Metabolism : TEM·Zhiyong Cheng
Nov 18, 2020·Proceedings of the National Academy of Sciences of the United States of America·Carlos CastañoMarcelina Párrizas

❮ Previous
Next ❯

Methods Mentioned

BETA
biopsies
Assay
RNAseq
immunoprecipitation
transfection

Software Mentioned

TargetScan
FASTX
Prism
Graph Pad
miraligner
ImageJ
- Toolkit

Related Concepts

Related Feeds

Aging & Diabetes

This feed focuses on the role of the aging process on developing diabetes.

Aging-Associated Metabolic Disorders

Age is associated with many metabolic disorders including cardiovascular diseases, type 2 diabetes, stroke and heart disease. The mediators in aging process have been suggested to play a part in the cellular processes responsible for these metabolic disorders. Here is the latest research on aging-associated metabolic disorders.