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

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Abstract

White adipose tissue (WAT) fibrosis occurring in obesity contributes to the inflammatory and metabolic co-morbidities of insulin resistance and type 2 diabetes, yet the mechanisms involved remain poorly understood. Here, we report a role for the broadly conserved microRNA 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 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 pro-fibrotic 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 anti-fibrotic 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