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Obesity of mice lacking VAP-1/SSAO by Aoc3 gene deletion is reproduced in mice expressing a mutated vascular adhesion protein-1 (VAP-1) devoid of amine oxidase activity

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Abstract

The product of Aoc3 gene is known as vascular adhesion protein-1 (VAP-1), a glycoprotein contributing to leukocyte extravasation and exhibiting semicarbazide-sensitive amine oxidase activity (SSAO). Regarding the immune functions of VAP-1/SSAO, it is known that mice bearing Aoc3 gene knock-out (AOC3KO) exhibit defects in leukocyte migration similar to those of mice expressing a mutated VAP-1 lacking functional SSAO activity (knock-in, AOC3KI). However, it has not been reported whether these models differ regarding other disturbances. Thus, we further compared endocrine-metabolic phenotypes of AOC3KO and AOC3KI mice to their respective control. Special attention was paid on adiposity, glucose and lipid handling, since VAP-1/SSAO is highly expressed in adipose tissue (AT). In both mouse lines, no tissue SSAO activity was found, while Aoc3 mRNA was absent in AOC3KO only. Although food consumption was unchanged, both AOC3KO and AOC3KI mice were heavier and fatter than their respective controls. Other alterations commonly found in adipocytes from both lines were loss of benzylamine insulin-like action with unchanged insulin lipogenic responsiveness and adiponectin expression. A similar downregulation of inflammatory markers (CD45, IL6) was found in AT. Glucose handling and liver mass remained unchanged, while circulating lipid profile was distinctly altered, with increased cholesterol in AOC3KO only. These results suggest that the lack of oxidase activity found in AOC3KI is sufficient to reproduce the metabolic disturbances observed in AOC3KO mice, save those related with cholesterol transport. Modulation of SSAO activity therefore constitutes a potential target for the treatment of cardiometabolic diseases, especially obesity when complicated by low-grade inflammation.

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Acknowledgements

The authors are grateful to all the other participants of the TUNEUP project and to the members of CTPIOD mini-network (http://obesitydiabetesinctp.weebly.com) for the helpful discussions. All our thanks to Iffiu-Soltesz Z., Mercader J. and Prévot D. (I2MC, Toulouse, France) for facilitating phenotypic explorations.

Funding

Preliminary part of this study was supported by European grants of the QLG1-CT-1999-00295 project.

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Authors and Affiliations

  1. Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Toulouse, France

    Valentin Jargaud, Sandy Bour, François Tercé, Xavier Collet, Philippe Valet, Anne Bouloumié & Christian Carpéné

  2. University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France

    Valentin Jargaud, Sandy Bour, François Tercé, Xavier Collet, Philippe Valet, Anne Bouloumié & Christian Carpéné

  3. Sanofi, Translational Sciences Unit, Chilly-Mazarin, France

    Valentin Jargaud & Jean-Claude Guillemot

  4. Dept. of Kinesiology, Fac. of Medicine and PEPS, Laval University, Québec, Canada

    Pascale Mauriège

  5. MediCity and Institute of Biomedicine, University of Turku, Turku, Finland

    Sirpa Jalkanen & Marko Salmi

  6. MediCity and Biotie Therapies Plc, Turku, Finland

    Craig Stolen & David J. Smith

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Correspondence to Christian Carpéné.

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All animal procedures complied with the principles established at INSERM and were performed in compliance with the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines. All protocols were approved by the CREFRE Ethics Committee (Centre Régional d’Exploration Fonctionnelle et Ressources Expérimentales, Toulouse, France) with agreement number C31 55507.

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Keypoints

• Aoc3 encodes for vascular adhesion protein/semicarbazide-sensitive amine oxidase.

• VAP-1/SSAO is a glycoprotein involved in lymphocyte trafficking and amine oxidation.

• Either Aoc3 knock-out or amine oxidase invalidation leads to obesity in mouse.

• Fat mass increases without inflammation but with possible changes in blood cholesterol.

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Jargaud, V., Bour, S., Tercé, F. et al. Obesity of mice lacking VAP-1/SSAO by Aoc3 gene deletion is reproduced in mice expressing a mutated vascular adhesion protein-1 (VAP-1) devoid of amine oxidase activity. J Physiol Biochem 77, 141–154 (2021). https://doi.org/10.1007/s13105-020-00756-y

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