Faculty, Staff and Student Publications

Language

English

Publication Date

8-1-2025

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI175566

PMID

40471675

PMCID

PMC12321386

PubMedCentral® Posted Date

6-5-2025

PubMedCentral® Full Text Version

Post-print

Abstract

White adipose tissue (WAT) fibrosis occurring in obesity contributes to the inflammatory and metabolic comorbidities of insulin resistance and type 2 diabetes, yet the mechanisms involved remain poorly understood. Here, we report a role for the broadly conserved miRNA miR-30a as a regulator of WAT fibrosis and systemic glucose metabolism. Mice modified to express miR-30a at elevated levels in adipose tissues maintain insulin sensitivity coupled with reduced fatty liver disease when fed a high-fat diet. These effects were attributable to cell-autonomous functions of miR-30a that potently increase expression of adipocyte-specific genes. Proteomic screening revealed miR-30a limits profibrotic programs in subcutaneous WAT, at least in part, by repressing PAI-1, a dominant regulator of fibrinolysis and biomarker of insulin resistance. Conversely, mouse adipocytes lacking miR-30a exhibited greater expression of fibrosis markers with disrupted cellular metabolism. Lastly, miR-30a expression negatively correlates with PAI-1 levels in subcutaneous WAT from people with obesity, further supporting an antifibrotic role for miR-30a. Together, these findings uncover miR-30a as a critical regulator of adipose tissue fibrosis that predicts metabolically healthy obesity in people and mice.

Keywords

MicroRNAs, Animals, Obesity, Mice, Fibrosis, Humans, Plasminogen Activator Inhibitor 1, Adipose Tissue, White, Insulin Resistance, Male, Mice, Knockout, Diet, High-Fat

Published Open-Access

yes

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