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Treatment with TUG891, a free fatty acid receptor 4 agonist, restores adipose tissue metabolic dysfunction following chronic sleep fragmentation in mice

International Journal of Obesity volume 40, pages 1143–1149 (2016)Cite this article

Subjects

Abstract

Background:

Sleep fragmentation (SF), a frequent occurrence in multiple sleep and other diseases leads to increased food intake and insulin resistance via increased macrophage activation and inflammation in visceral white adipose tissue (VWAT). Free fatty acid receptor 4 (FFA4) is reduced in pediatric sleep apnea patients and FFA4 agonists have been proposed in the treatment of obesity and metabolic dysfunction.

Methods:

Male mice were subjected to SF exposures for 6 weeks, and treated during the last 2 weeks with either TUG891, a potent and selective FFA4 agonist, or vehicle (Veh). Glucose and insulin tolerance tests and VWAT insulin sensitivity tests were conducted (phosphorylated Akt/total Akt), along with flow cytometric assessments of VWAT macrophage polarity, and T-cell lymphocyte subsets.

Results:

SF-TUG891 mice showed reduction in food consumption, weight gain and VWAT mass. Furthermore, TUG891 treatment ameliorated glucose tolerance test and insulin tolerance test responses and increased VWAT p-Akt/Akt responses to insulin. Increases in M1/M2 macrophages and decreased Treg counts in VWAT associated with SF were markedly improved by TUG891, and VWAT macrophages from TUG891-treated mice had markedly attenuated insulin resistance effects on naïve cultured adipocytes.

Conclusions:

Treatment with an FFA4 agonist reverses SF-induced food intake increases and gains in body weight, and significantly attenuates VWAT inflammation and insulin resistance. Thus, interventional dietary or pharmaceutical strategies aimed at increasing FFA4 activity may serve as potentially useful adjunctive therapies for sleep disorders accompanied by metabolic morbidity.

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Author information

Authors and Affiliations

  1. Department of Pediatrics, Biological Sciences Division, Section of Pediatric Sleep Medicine, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA

    D Gozal, Z Qiao, I Almendros, J Zheng & A Khalyfa

  2. Departments of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark

    B Shimpukade & T Ulven

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  1. D Gozal
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  2. Z Qiao
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Corresponding author

Correspondence to D Gozal.

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Author contributions

ZQ performed experiments and served as blinded observer. IA and JZ performed experiments. TU provided access to the FFA4 agonist and participated in the initial design planning of the project. BS synthesized the FFA4 agonist for the study. DG was the originator of the project, provided critical supervision during all phases of the experiments, analyzed data, drafted the initial and subsequent versions of the manuscript and is responsible for the financial support of the project and the manuscript content. All authors have reviewed and approved the final version of the manuscript. DG is the guarantor for this work, and takes full responsibility for the work as a whole, including the study design, access to data and the decision to submit and publish the manuscript.

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Gozal, D., Qiao, Z., Almendros, I. et al. Treatment with TUG891, a free fatty acid receptor 4 agonist, restores adipose tissue metabolic dysfunction following chronic sleep fragmentation in mice. Int J Obes 40, 1143–1149 (2016). https://doi.org/10.1038/ijo.2016.37

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