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Clinical Research

F13A1 transglutaminase expression in human adipose tissue increases in acquired excess weight and associates with inflammatory status of adipocytes

International Journal of Obesity volume 45, pages 577–587 (2021)Cite this article

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Abstract

Objective

F13A1/FXIII-A transglutaminase has been linked to adipogenesis in cells and to obesity in humans and mice, however, its role and associated molecular pathways in human acquired excess weight have not been explored.

Methods

We examined F13A1 expression and association to human weight gain in weight-discordant monozygotic twins (Heavy-Lean difference (ΔWeight, 16.8 kg ± 7.16 for n = 12). The twin pairs were examined for body composition (by dual-energy X-ray absorptiometry), abdominal body fat distribution (by magnetic resonance imaging), liver fat content (by magnetic resonance spectroscopy), circulating adipocytokines, leptin and adiponectin, as well as serum lipids. Affymetrix full transcriptome mRNA analysis was performed from adipose tissue and adipocyte-enriched fractions from subcutaneous abdominal adipose tissue biopsies. F13A1 differential expression between the heavy and lean co-twins was examined and its correlation transcriptome changes between co-twins were performed.

Results

F13A1 mRNA showed significant increase in adipose tissue (p < 0.0001) and an adipocyte-enriched fraction (p = 0.0012) of the heavier co-twin. F13A1 differential expression in adipose tissue (Heavy-Lean ΔF13A1) showed significant negative correlation with circulating adiponectin (p = 0.0195) and a positive correlation with ΔWeight (p = 0.034), ΔBodyFat (0.044) and ΔAdipocyte size (volume, p = 0.012;) in adipocyte-enriched fraction. A whole transcriptome-wide association study (TWAS) on ΔF13A1 vs weight-correlated ΔTranscriptome identified 182 F13A1-associated genes (r > 0.7, p = 0.05) with functions in several biological pathways including cell stress, inflammatory response, activation of cells/leukocytes, angiogenesis and extracellular matrix remodeling. F13A1 did not associate with liver fat accumulation.

Conclusions

F13A1 levels in adipose tissue increase with acquired excess weight and associate with pro-inflammatory, cell stress and tissue remodeling pathways. This supports its role in expansion and inflammation of adipose tissue in obesity.

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Fig. 1: F13A1 expression in adipose tissue and adipocyte-enriched fraction of weight-discordant monozygotic (MZ) twin pairs.
Fig. 2: Significant correlation (r) of differential (Δ Heavy-Lean) F13A1 expression in adipose tissue and adipocyte-enriched fraction to differential (Δ Heavy-Lean) metabolic parameters relevant to energy metabolism in weight-discordant monozygotic (MZ) twin pairs.
Fig. 3: Linear correlation (r2) of differential F13A1 expression (Δ) in an adipocyte-enriched fraction of weight-discordant monozygotic (MZ) twin pairs with selected genes (ΔHeavy-Lean twin) that represent significant, over-represented GOterms listed in Table 2.
Fig. 4: F13A1 expression in weight-discordant monozygotic (MZ) twin pairs with liver fat % (LF%) discordance.

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Acknowledgements

This study was supported by grants to MTK from the Canadian Institutes of Health Research (CIHR) (MOP-119403). MA is supported by an internal stipend, Nyman Award, from the Faculty of Medicine of McGill University. AH is a summer scholar of McGill Initiative in Computational Medicine. AB is supported by Healthy Brains for Healthy Lives initiative at McGill University. SH was supported by Finnish Diabetes Research Foundation, Emil Aaltonen Foundation, Finnish Medical Foundation and Helsinki University Hospital funds. KHP is funded by the Academy of Finland, grant numbers 314383, 266286 and the Academy of Finland, Centre of Excellence in Research on Mitochondria, Metabolism and Disease (FinMIT), grant number 272376; Finnish Medical Foundation; Gyllenberg Foundation; Novo Nordisk Foundation, grant numbers NNF17OC0027232, NNF10OC1013354; Finnish Diabetes Research Foundation; Finnish Foundation for Cardiovascular Research; University of Helsinki, Government Research Funds and Helsinki University Hospital.

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Authors and Affiliations

  1. Faculty of Medicine (Division of Experimental Medicine), McGill University, Montreal, QC, Canada

    M. T. Kaartinen, M. Arora & A. Hang

  2. Faculty of Dentistry (Biomedical Sciences), McGill University, Montreal, QC, Canada

    M. T. Kaartinen

  3. Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland

    S. Heinonen, A. Rissanen & K. H. Pietiläinen

  4. Departments of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada

    A. Barry

  5. Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada

    A. Barry

  6. Obesity Center, Abdominal Center, Endocrinology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

    J. Lundbom, A. Hakkarainen, N. Lundholm & K. H. Pietiläinen

  7. Department of Public Health, Finnish Twin Cohort Study, University of Helsinki, Helsinki, Finland

    J. Kaprio

  8. Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland

    J. Kaprio

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  1. M. T. Kaartinen
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Kaartinen, M.T., Arora, M., Heinonen, S. et al. F13A1 transglutaminase expression in human adipose tissue increases in acquired excess weight and associates with inflammatory status of adipocytes. Int J Obes 45, 577–587 (2021). https://doi.org/10.1038/s41366-020-00722-0

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