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The role of adipose tissue and subsequent liver tissue hypoxia in obesity and early stage metabolic dysfunction associated steatotic liver disease

International Journal of Obesity volume 48, pages 512–522 (2024)Cite this article

Subjects

Abstract

Background

Obesity is linked to several health complication, including Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD). Adipose tissue hypoxia has been suggested as an important player in the pathophysiological mechanism leading to chronic inflammation in obesity, and in the progression of MASLD. The study aims to investigate the effect of progressive obesity on adipose and liver tissue hypoxia.

Methods

Male 8-week-old C57BL/6J mice were fed a high-fat high-fructose diet (HFHFD) or control diet (CD) for 4, 8, 12, 16 and 20 weeks. Serum ALT, AST and lipid levels were determined, and glucose and insulin tolerance testing was performed. Liver, gonadal and subcutaneous adipose tissue was assessed histologically. In vivo tissue pO2 measurements were performed in gonadal adipose tissue and liver under anesthesia. A PCR array for hypoxia responsive genes was performed in liver and adipose tissue. The main findings in the liver were validated in another diet-induced MASLD mice model, the choline-deficient L–amino acid defined high-fat diet (CDAHFD).

Results

HFHFD feeding induced a progressive obesity, dyslipidaemia, insulin resistance and MASLD. In vivo pO2 was decreased in gonadal adipose tissue after 8 weeks of HFHFD compared to CD, and decreased further until 20 weeks. Liver pO2 was only significantly decreased after 16 and 20 weeks of HFHFD. Gene expression and histology confirmed the presence of hypoxia in liver and adipose tissue. Hypoxia could not be confirmed in mice fed a CDAHFD.

Conclusion

Diet-induced obesity in mice is associated with hypoxia in liver and adipose tissue. Adipose tissue hypoxia develops early in obesity, while liver hypoxia occurs later in the obesity development but still within the early stages of MASLD. Liver hypoxia could not be directly confirmed in a non-obese liver-only MASLD mice model, indicating that obesity-related processes such as adipose tissue hypoxia are important in the pathophysiology of obesity and MASLD.

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Fig. 1: Body weight evolution over time.
Fig. 2: Histology of the liver.
Fig. 3: Evolution of pO2 in liver and adipose tissue.
Fig. 4: Effect of covariates on gene expression.
Fig. 5: Relationship between in vivo hypoxia and gene expression.
Fig. 6: Hypoxia signature.

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Data availability

The raw data supporting the conclusions of this article will be made available from the corresponding authors, without undue reservation on reviewers’ request.

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Acknowledgements

We would like to thank the department of Forensic Medicine of the Antwerp University Hospital for providing the equipment and assistance in conducting the PCR arrays. We would also like to thank all lab technicians of the Laboratory of Experimental Medicine and Pediatrics for their assistance during the different phases of this project.

Author contribuions

AVE conceptualization, methodology, formal analysis, investigation, writing original draft, project administration, funding acquisition; WK methodology, writing – review & editing; CP investigation, writing – review & editing; SM investigation, writing – review & editing; SVL formal analysis, writing – review & editing; KVDM writing – review & editing; KVH writing – review & editing; JDM methodology, writing – review & editing; BDW methodology, writing – review & editing, supervision; SF conceptualization, methodology, writing – review & editing, supervision; SV conceptualization, writing – review & editing, supervision, funding acquisition.

Funding

Funding was received by an Unrestricted Research Grant of the American Thoracic Society Foundation, but this organization had no conflict of interest with the result, nor a role in the study design.

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Authors and Affiliations

  1. Laboratory of Experimental Medicine and Pediatrics and member of the Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium

    Annelies Van Eyck, Wilhelmus J. Kwanten, Cédric Peleman, Sanae Makhout, Karolien Van De Maele, Kim Van Hoorenbeeck, Joris De Man, Benedicte Y. De Winter, Sven Francque & Stijn L. Verhulst

  2. Department of Pediatrics, Antwerp University Hospital, Edegem, Belgium

    Annelies Van Eyck, Karolien Van De Maele, Kim Van Hoorenbeeck & Stijn L. Verhulst

  3. Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium

    Wilhelmus J. Kwanten, Cédric Peleman, Benedicte Y. De Winter & Sven Francque

  4. Center of Oncological Research (CORE), MIPRO, IPPON, University of Antwerp, Antwerp, Belgium

    Steven Van Laere

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Van Eyck, A., Kwanten, W.J., Peleman, C. et al. The role of adipose tissue and subsequent liver tissue hypoxia in obesity and early stage metabolic dysfunction associated steatotic liver disease. Int J Obes 48, 512–522 (2024). https://doi.org/10.1038/s41366-023-01443-w

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