The microRNA miR-30a blocks adipose tissue fibrosis accumulation in obesity
Pradip K. Saha, Robert Sharp, Aaron R. Cox, Rabie Habib, Michael J. Bolt, Jessica B. Felix, Claudia E. Ramirez Bustamante, Xin Li, Sung Yun Jung, Kang Ho Kim, Kai Sun, Huaizhu Wu, Samuel Klein, Sean M. Hartig
Pradip K. Saha, Robert Sharp, Aaron R. Cox, Rabie Habib, Michael J. Bolt, Jessica B. Felix, Claudia E. Ramirez Bustamante, Xin Li, Sung Yun Jung, Kang Ho Kim, Kai Sun, Huaizhu Wu, Samuel Klein, Sean M. Hartig
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Research Article Cell biology Metabolism

The microRNA miR-30a blocks adipose tissue fibrosis accumulation in obesity

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.

Authors

Pradip K. Saha, Robert Sharp, Aaron R. Cox, Rabie Habib, Michael J. Bolt, Jessica B. Felix, Claudia E. Ramirez Bustamante, Xin Li, Sung Yun Jung, Kang Ho Kim, Kai Sun, Huaizhu Wu, Samuel Klein, Sean M. Hartig

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Figure 4

Local antifibrotic effects associated with enforced miR-30a expression in subcutaneous WAT of obese mice.

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Local antifibrotic effects associated with enforced miR-30a expression i...
(A) Gene set enrichment analysis (GSEA) of altered proteins (*P < 0.05 for miR-30afat/miR-30aL/L; n = 4/group) identified signatures depleted by transgenic miR-30a expression in the iWAT of obese mice. (B) iWAT protein lysates (pooled n = 4/group) were incubated with cytokine arrays to follow up the proteomic screen. (C) Sirius red staining in the iWAT and eWAT after HFD feeding for 18 weeks. Scale bars: 50 μm. eWAT and iWAT (D) quantification of percentage of Picrosirius red staining (%area; n = 3–4/group) and hydroxyproline content (E) by mass spectrometry (n = 6/group, relative to miR-30aL/L). Expression profiles of profibrotic (F), STAT1 targets (G), and metabolic genes (H) (n = 6/group) in the iWAT and eWAT after HFD feeding for 18 weeks (n = 6/group). (I) Western blotting with indicated antibodies and associated quantification (J) to validate changes in fibrosis markers with independent WAT protein lysates. HSP90 and β-actin served as invariant protein controls. All data are represented as the mean ± SEM. *P < 0.05 and #P < 0.10, by 2-tailed, unpaired Student’s t test (D–H and J). Rel, relative.