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Adipocyte GPX4 protects against inflammation, hepatic insulin resistance and metabolic dysregulation

International Journal of Obesity volume 46, pages 951–959 (2022)Cite this article

Subjects

Abstract

Objectives

Metabolic inflammation is a hallmark of obesity and related disorders, afflicting substantial morbidity and mortality to individuals worldwide. White visceral and subcutaneous adipose tissue not only serves as energy storage but also controls metabolism. Adipose tissue inflammation, commonly observed in human obesity, is considered a critical driver of metabolic perturbation while molecular hubs are poorly explored. Metabolic stress evoked by e.g. long-chain fatty acids leads to oxidative perturbation of adipocytes and production of inflammatory cytokines, fuelling macrophage infiltration and systemic low-grade inflammation. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation, accumulation of oxygen-specific epitopes and cell death, collectively referred to as ferroptosis. Here, we explore the function of adipocyte GPX4 in mammalian metabolism.

Methods

We studied the regulation and function of GPX4 in differentiated mouse adipocytes derived from 3T3-L1 fibroblasts. We generated two conditional adipocyte-specific Gpx4 knockout mice by crossing Gpx4fl/fl mice with Adipoq-Cre+ (Gpx4−/−AT) or Fabp4-Cre+ (Gpx4+/−Fabp4) mice. Both models were metabolically characterized by a glucose tolerance test and insulin resistance test, and adipose tissue lipid peroxidation, inflammation and cell death were assessed by quantifying oxygen-specific epitopes, transcriptional analysis of chemokines, quantification of F4/80+ macrophages and TUNEL labelling.

Results

GPX4 expression was induced during and required for adipocyte differentiation. In mature adipocytes, impaired GPX4 activity spontaneously evoked lipid peroxidation and expression of inflammatory cytokines such as TNF-α, interleukin 1β (IL-1β), IL-6 and the IL-8 homologue CXCL1. Gpx4−/−AT mice spontaneously displayed adipocyte hypertrophy on a chow diet, which was paralleled by the accumulation of oxygen-specific epitopes and macrophage infiltration in adipose tissue. Furthermore, Gpx4−/−AT mice spontaneously developed glucose intolerance, hepatic insulin resistance and systemic low-grade inflammation, when compared to wildtype littermates, which was similarly recapitulated in Gpx4+/−Fabp4 mice. Gpx4−/−AT mice exhibited no signs of adipocyte death.

Conclusion

Adipocyte GPX4 protects against spontaneous metabolic dysregulation and systemic low-grade inflammation independent from ferroptosis, which could be therapeutically exploited in the future.

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Fig. 1: GPX4 is required for adipocyte differentiation and suppresses cytokine production.
Fig. 2: Adipocyte GPX4 protects against adipose tissue inflammation.
Fig. 3: Adipocyte GPX4 protects against spontaneous metabolic dysregulation.
Fig. 4: Spontaneous metabolic dysregulation is recapitulated in Gpx4+/−Fabp4 mice.

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Acknowledgements

We are grateful for the support received from the Austrian Science Fund (FWF P33070) (to TEA). We appreciate the support of the Christian Doppler Research Foundation and the Austrian Federal Ministry of Science, Research and Economy and the National Foundation for Research, Technology and Development (to SK). We thank for the financial support of the Excellence Initiative (Competence Centres for Excellent Technologies—COMET) of the Austrian Research Promotion Agency FFG: Research Centre of Excellence in Vascular Ageing Tyrol, VASCage (K-Project Nr. 843536) funded by BMVIT, BMWFW, Wirtschaftsagentur Wien and Standortagentur Tirol (to HT). We are grateful for the support from the Austrian Society of Gastroenterology and Hepatology (ÖGGH) (to LM). We thank for the support from the Tyrolean Science Fund (TWF) (to FG).

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  1. These authors contributed equally: Julian Schwärzler, Lisa Mayr, Susanne Kaser & Timon E. Adolph

Authors and Affiliations

  1. Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, Medical University of Innsbruck, Innsbruck, Austria

    Julian Schwärzler, Lisa Mayr, Bernhard Radlinger, Felix Grabherr, Maureen Philipp, Bernhard Texler, Christoph Grander, Andreas Ritsch, Monika Hunjadi, Barbara Enrich, Karin Salzmann, Herbert Tilg, Susanne Kaser & Timon E. Adolph

  2. Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA

    Qitao Ran

  3. Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria

    Lukas A. Huber

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Contributions

JS and LM designed, performed and analysed most experiments and helped prepare the manuscript together with and BR, FG, MP, BT, CG, BE and KS. AR and MH performed cholesterol quantification. QR and LAH provided an essential mouse model. HT, SK and TEA coordinated the project and prepared the manuscript together with JS and LM.

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Correspondence to Timon E. Adolph.

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Schwärzler, J., Mayr, L., Radlinger, B. et al. Adipocyte GPX4 protects against inflammation, hepatic insulin resistance and metabolic dysregulation. Int J Obes 46, 951–959 (2022). https://doi.org/10.1038/s41366-022-01064-9

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