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Animal Models

Inhibition of myostatin in mice improves insulin sensitivity via irisin-mediated cross talk between muscle and adipose tissues

International Journal of Obesity volume 40, pages 434–442 (2016)Cite this article

Subjects

Abstract

Background/Objective:

In mice, a high-fat diet (HFD) induces obesity, insulin resistance and myostatin production. We tested whether inhibition of myostatin in mice can reverse these HFD-induced abnormalities.

Subjects/Methods:

C57BL/6 mice were fed a HFD for 16 weeks including the final 4 weeks some mice were treated with an anti-myostatin peptibody. Body composition, the respiratory exchange ratio plus glucose and insulin tolerance tests were examined. Myostatin knock down in C2C12 cells was performed using small hairpin RNA lentivirus. Adipose tissue-derived stem cells were cultured to measure their responses to conditioned media from C2C12 cells lacking myostatin, or to recombinant myostatin or irisin. Isolated peritoneal macrophages were treated with myostatin or irisin to determine whether myostatin or irisin induce inflammatory mechanisms.

Results:

In HFD-fed mice, peptibody treatment stimulated muscle growth and improved insulin resistance. The improved glucose and insulin tolerances were confirmed when we found increased muscle expression of p-Akt and the glucose transporter, Glut4. In HFD-fed mice, the peptibody suppressed macrophage infiltration and the expression of proinflammatory cytokines in both the muscle and adipocytes. Inhibition of myostatin caused the conversion of white (WAT) to brown adipose tissue, whereas stimulating fatty acid oxidation and increasing energy expenditure. The related mechanism is a muscle-to-fat cross talk mediated by irisin. Myostatin inhibition increased peroxisome proliferator-activated receptor gamma, coactivator 1α expression and irisin production in the muscle. Irisin then stimulated WAT browning. Irisin also suppresses inflammation and stimulates macrophage polarization from M1 to M2 types.

Conclusions:

These results uncover a metabolic pathway from an increase in myostatin that suppresses irisin leading to the activation of inflammatory cytokines and insulin resistance. Thus, myostatin is a potential therapeutic target to treat insulin resistance of type II diabetes as well as the shortage of brown/beige fat in obesity.

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Acknowledgements

This work was supported by the National Institutes of Health grant, R37 DK37175, to WEM, the National Natural Science Foundation of China (81401780) and Beijing Municipal Natural Science Foundation (5152007). We also acknowledge the generous support of Dr and Mrs Harold Selzman, the Norman S Coplon extramural research grant from the Satellite Health, American Diabetic Association (1-11-BS-194) and pilot/feasibility award of the Diabetes Research Center (P30-DK079638) to LZ.

Author contributions

JD, YD and LZ conceived and designed the experiments; JD, YD, YLD and LZ performed the experiments; JD, YD, LZ analyzed the data; WEM, CF and LZ wrote the paper.

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Author notes

  1. J Dong and Y Dong: These authors contributed equally to this work.

Authors and Affiliations

  1. College of Life Sciences, Sichuan University, Chengdu, China

    J Dong & F Chen

  2. Nephrology Division, Department of Medicine, Selzman Institute for Kidney Health, Baylor College of Medicine, Houston, TX, USA

    J Dong, Y Dong, Y Dong, W E Mitch & L Zhang

  3. Department of Cardiovascular Biology, Beijing Institutes of Heart, Lung, and Blood Vessel Diseases, An Zhen Hospital Affiliated to Capital Medical University, Beijing, China

    Y Dong

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Correspondence to F Chen or L Zhang.

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Dong, J., Dong, Y., Dong, Y. et al. Inhibition of myostatin in mice improves insulin sensitivity via irisin-mediated cross talk between muscle and adipose tissues. Int J Obes 40, 434–442 (2016). https://doi.org/10.1038/ijo.2015.200

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