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Updated: Nov 29, 2025

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miR-146a regulates insulin sensitivity via NPR3.

Julian Roos1,2, Meike Dahlhaus1,2, Jan-Bernd Funcke1,2,3

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MicroRNA-146a (miR-146a) deficiency worsens obesity and insulin resistance by promoting inflammation in white adipose tissue. Downregulation of natriuretic peptide receptor 3 (NPR3) by miR-146a is key to regulating insulin sensitivity.

Keywords:
AdipocyteInsulin resistanceNPR3microRNA

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Area of Science:

  • Metabolic disease pathogenesis
  • Adipose tissue biology
  • MicroRNA regulation

Background:

  • Obesity-related metabolic diseases involve white adipose tissue (WAT) inflammation.
  • Molecular mechanisms linking WAT inflammation and metabolic dysfunction are not fully understood.
  • MicroRNA-146a (miR-146a) is known to regulate inflammatory signaling pathways.

Purpose of the Study:

  • To investigate the role of miR-146a in obesity and associated insulin resistance.
  • To elucidate the molecular targets and pathways regulated by miR-146a in adipocytes.

Main Methods:

  • Utilized miR-146a knockout (KO) mice fed a high-fat diet (HFD).
  • Performed metabolic testing and white adipose tissue (WAT) transcriptomics in KO mice.
  • Conducted gain- and loss-of-function studies in human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes.
  • Identified miR-146a targets using CRISPR/Cas9 gene editing.

Main Results:

  • miR-146a KO mice exhibited increased body weight gain, fat mass, and adipocyte hypertrophy on HFD.
  • Exacerbated liver steatosis, insulin resistance, and glucose intolerance were observed in KO mice.
  • Inhibition of miR-146a in adipocytes reduced insulin-stimulated glucose uptake; miR-146a mimics increased it.
  • Natriuretic peptide receptor 3 (NPR3) was identified as a direct miR-146a target; NPR3 knockout enhanced glucose uptake and lipogenesis.

Conclusions:

  • MiR-146a plays a critical role in regulating systemic and adipocyte insulin sensitivity.
  • MiR-146a exerts its effects, in part, through the downregulation of natriuretic peptide receptor 3 (NPR3).
  • Targeting miR-146a or NPR3 may offer therapeutic strategies for obesity-related metabolic dysfunction.