Adipose tissue macrophage infiltration and hepatocyte stress increase GDF-15 throughout development of obesity to MASH
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.
Authors
- Bart Staels (ORCID: https://orcid.org/0000-0002-3784-1503)
- B. L. Legendre (ORCID: https://orcid.org/0000-0001-7903-0218)
- David Dombrowicz (ORCID: https://orcid.org/0000-0002-0485-8923)
- François Pattou (ORCID: https://orcid.org/0000-0001-8388-3766)
- Valentine Guinot
- Sandrine Quemener (ORCID: https://orcid.org/0000-0001-6369-3906)
- Robert Caïazzo (ORCID: https://orcid.org/0000-0001-5383-0540)
- Jacques Piette (ORCID: https://orcid.org/0000-0002-4898-6556)
- Violeta Raverdy (ORCID: https://orcid.org/0000-0001-5754-2028)
- Sylvie Legrand-Poels
- Hélène Verkindt (ORCID: https://orcid.org/0000-0002-4776-3350)
- Benan Pelin Sermikli (ORCID: https://orcid.org/0000-0001-9930-1919)
- Joel T. Haas (ORCID: https://orcid.org/0000-0002-0028-5988)
- Laurent L’homme (ORCID: https://orcid.org/0000-0002-5069-1837)
- Sébastien Fleury (ORCID: https://orcid.org/0000-0002-0679-3086)
- Nathalie Esser (ORCID: https://orcid.org/0000-0003-1823-3817)
- Lydie Cheval (ORCID: https://orcid.org/0000-0003-2957-6487)
- Emelie Barreby (ORCID: https://orcid.org/0000-0002-6467-5280)
- Myriam Aouadi (ORCID: https://orcid.org/0000-0001-6256-7107)
- Nicolas Paquot
Institutions
- Centre National de la Recherche Scientifique (FR)
- Karolinska University Hospital (SE)
- Inserm (FR)
- University of Liège (BE)
- Université Paris Cité (FR)
- Université de Lille (FR)
- Institut Pasteur de Lille (FR)
- Karolinska Institutet (SE)
- Centre Hospitalier Universitaire de Lille (FR)
- Sorbonne Université (FR)
- Centre de Recherche des Cordeliers (FR)
- Metabolism and Renal Physiology (FR)
- European Genomic Institute for Diabetes (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-21
- DOI
- https://doi.org/10.1038/s41467-024-51078-2
- Citations
- 28
- Primary Topic
- GDF15 and Related Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 13.16
Funders
- European Genomic Institute for Diabetes
- Agence Nationale de la Recherche
- Fonds De La Recherche Scientifique - FNRS