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

Mol Metab. 2018 Nov;17:49-60. doi: 10.1016/j.molmet.2018.08.003. Epub 2018 Aug 11.

Abstract

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.

Keywords: Genetics; Glucose production; Insulin resistance; Liver metabolism; Transcriptional regulation; Type 2 diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Diabetes Mellitus, Type 2 / metabolism
  • Diet, High-Fat
  • Female
  • Forkhead Transcription Factors / antagonists & inhibitors
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Glucose / biosynthesis
  • Hepatocytes / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin Resistance / genetics*
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Obese
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Middle Aged
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction

Substances

  • Forkhead Transcription Factors
  • Insulin
  • MIRN205 microRNA, human
  • MIRN205 microRNA, mouse
  • MicroRNAs
  • Proto-Oncogene Proteins c-akt
  • Glucose