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Adipose tissue macrophage infiltration and hepatocyte stress increase GDF-15 throughout development of obesity to MASH

Author

Listed:
  • Laurent L’homme

    (Institut Pasteur de Lille, U1011-EGID)

  • Benan Pelin Sermikli

    (Institut Pasteur de Lille, U1011-EGID)

  • Joel T. Haas

    (Institut Pasteur de Lille, U1011-EGID)

  • Sébastien Fleury

    (Institut Pasteur de Lille, U1011-EGID)

  • Sandrine Quemener

    (Institut Pasteur de Lille, U1011-EGID)

  • Valentine Guinot

    (Institut Pasteur de Lille, U1011-EGID)

  • Emelie Barreby

    (Karolinska University Hospital)

  • Nathalie Esser

    (University of Liège
    CHU Liège)

  • Robert Caiazzo

    (U1190-EGID (Translational research in Diabetes))

  • Hélène Verkindt

    (U1190-EGID (Translational research in Diabetes))

  • Benjamin Legendre

    (U1190-EGID (Translational research in Diabetes))

  • Violeta Raverdy

    (U1190-EGID (Translational research in Diabetes))

  • Lydie Cheval

    (Laboratoire de Physiologie Rénale et Tubulopathies
    CNRS EMR 8228—Unité Métabolisme et Physiologie Rénale)

  • Nicolas Paquot

    (University of Liège
    CHU Liège)

  • Jacques Piette

    (University of Liège)

  • Sylvie Legrand-Poels

    (University of Liège)

  • Myriam Aouadi

    (Karolinska University Hospital)

  • François Pattou

    (U1190-EGID (Translational research in Diabetes))

  • Bart Staels

    (Institut Pasteur de Lille, U1011-EGID)

  • David Dombrowicz

    (Institut Pasteur de Lille, U1011-EGID)

Abstract

Plasma growth differentiation factor-15 (GDF-15) levels increase with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) but the underlying mechanism remains poorly defined. Using male mouse models of obesity and MASLD, and biopsies from carefully-characterized patients regarding obesity, type 2 diabetes (T2D) and MASLD status, we identify adipose tissue (AT) as the key source of GDF-15 at onset of obesity and T2D, followed by liver during the progression towards metabolic dysfunction-associated steatohepatitis (MASH). Obesity and T2D increase GDF15 expression in AT through the accumulation of macrophages, which are the main immune cells expressing GDF15. Inactivation of Gdf15 in macrophages reduces plasma GDF-15 concentrations and exacerbates obesity in mice. During MASH development, Gdf15 expression additionally increases in hepatocytes through stress-induced TFEB and DDIT3 signaling. Together, these results demonstrate a dual contribution of AT and liver to GDF-15 production in metabolic diseases and identify potential therapeutic targets to raise endogenous GDF-15 levels.

Suggested Citation

  • Laurent L’homme & Benan Pelin Sermikli & Joel T. Haas & Sébastien Fleury & Sandrine Quemener & Valentine Guinot & Emelie Barreby & Nathalie Esser & Robert Caiazzo & Hélène Verkindt & Benjamin Legendre, 2024. "Adipose tissue macrophage infiltration and hepatocyte stress increase GDF-15 throughout development of obesity to MASH," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51078-2
    DOI: 10.1038/s41467-024-51078-2
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