Theranostics 2018; 8(8):2171-2188. doi:10.7150/thno.22565

Research Paper

Adipocyte-Derived Exosomal MiR-27a Induces Insulin Resistance in Skeletal Muscle Through Repression of PPARγ

Yang Yu1, Hongwei Du2, Shengnan Wei1, Linjing Feng1, Junnan Li1, Fan Yao1, Ming Zhang1*✉, Grant M. Hatch3, Li Chen1*✉

1. Department of Pharmacology, College of Basic Medical Sciences, School of nursing, Jilin University, Changchun 130021, China
2. Research Institution of Paediatrics, Department of Pediatric Endocrinology, The First Clinical Hospital Affiliated to Jilin University, Changchun, Jilin 130021, China
3. DREAM, Children's Hospital Research Institute of Manitoba, Center for Research and Treatment of Atherosclerosis, Department of Pharmacology & Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada.
*Both authors contributed equally to this work

Abstract

The mechanism by which adipocyte-derived endocrine factors promote insulin resistance in skeletal muscle are not fully understood. MiR-27a is highly expressed in sera of obese individuals with prediabetes and T2DM, and mainly derived by adipose tissues. Thus, miR-27a secreted into circulation by adipose tissue may regulate insulin resistance in skeletal muscle.

Methods: The association between miR-27a and insulin resistance in skeletal muscle was determined in obese children, high-fat diet-induced miR-27a knockdown obese mice, db/db mice and C2C12 cells overexpressing miR-27a. The crosstalk mediated by exosomal miR-27a between adipose tissue and skeletal muscle was determined in C2C12 cells incubated with conditioned medium prepared from palmitate-treated 3T3-L1 adipocytes.

Results: We showed that serum miR-27a level correlated positively with obesity and insulin resistance in obese children, and that elevated serum miR-27a levels correlated with insulin resistance in leptin receptor-deficient db/db mice, and with obesity and insulin resistance in high-fat diet-fed C57BL/6J mice. MiR-27a released from adipocytes of high-fat diet-fed C57BL/6J mice was associated with triglyceride accumulation. MiR-27a derived from these adipocytes induced insulin resistance in C2C12 skeletal muscle cells through miR-27a-mediated repression of PPARγ and its downstream genes involved in the development of obesity.

Conclusions: These results identify a novel crosstalk signaling pathway between adipose tissue and skeletal muscle in the development of insulin resistance, and indicate that adipose tissue-derived miR-27a may play a key role in the development of obesity-triggered insulin resistance in skeletal muscle.

Keywords: miR-27a, adipocyte, skeletal muscle, insulin resistance, exosome, PPARγ

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How to cite this article:
Yu Y, Du H, Wei S, Feng L, Li J, Yao F, Zhang M, Hatch GM, Chen L. Adipocyte-Derived Exosomal MiR-27a Induces Insulin Resistance in Skeletal Muscle Through Repression of PPARγ. Theranostics 2018; 8(8):2171-2188. doi:10.7150/thno.22565. Available from http://www.thno.org/v08p2171.htm