Chronic hyperinsulinemia induced miR-27b is linked to adipocyte insulin resistance by targeting insulin receptor

Ankita Srivastava, Kripa Shankar, Muheeb Beg, Sujith Rajan, Abhishek Gupta, Salil Varshney, Durgesh Kumar, Sanchita Gupta, Raj Kumar Mishra, Anil Nilkanth Gaikwad

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Abstract: Defect in insulin signaling leads to the development of insulin resistance followed by type 2 diabetes. Exploiting our previously developed physiological chronic hyperinsulinemia (CI)-mediated insulin resistance (IR) model, we wanted to understand how miRNAs contribute to the development of IR. Amongst the identified and validate miRNAs, the expression of miR-27b was found to be highly upregulated during CI-induced IR in 3T3-L1 adipocytes. We also validated the expression of miR-27b in CI-induced IR in human mesenchymal stem cell (hMSC)-derived adipocytes and in vivo high fat diet (HFD)-induced IR mice model. Bioinformatics target prediction softwares and luciferase reporter assay identified insulin receptor (INSR) as one of a prime target of miR-27b. Lentiviral mediated overexpression of miR-27b impairs insulin signaling by modulating INSR expression that in turn led to decreased glucose uptake in both 3T3-L1 and hMSC-derived adipocytes. Conversely, inhibition of miR-27b reversed CI-mediated suppression of target protein INSR and improved phosphorylation of Akt, a nodal protein of insulin signaling that is impaired by CI treatment. Lentiviral mediated overexpression of miR-27b in in vivo C57BL/6 mice impaired whole body glucose tolerance and adipose tissue insulin sensitivity. Furthermore, inhibition of miR-27b in HFD-induced insulin resistance mice model improved glucose tolerance and adipose tissue insulin sensitivity by increasing the expression of its target gene INSR in eWAT. Thus, our results indicate that miR-27b functions as a prime modulator of CI-induced IR via regulating the expression of INSR. Key messages: miR-27b is upregulated in different in vitro and in vivo models of insulin resistance.miR-27b directly suppresses the expression of INSR by targeting 3’UTR of INSR.Modulation of miR-27b expression regulates insulin sensitivity by targeting INSR.

Original languageEnglish (US)
Pages (from-to)315-331
Number of pages17
JournalJournal of Molecular Medicine
Volume96
Issue number3-4
DOIs
StatePublished - Apr 1 2018
Externally publishedYes

Keywords

  • Chronic hyperinsulinemia
  • High fat diet
  • Insulin receptor
  • Insulin resistance
  • miR-27b

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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