miR-146a regulates insulin sensitivity via NPR3

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.