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

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, Violeta Raverdy, Lydie Cheval, Nicolas Paquot, Jacques Piette, Sylvie Legrand-Poels, Myriam Aouadi, François Pattou, Bart Staels and David Dombrowicz ()
Additional contact information
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
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
Nicolas Paquot: University of 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

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51078-2

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