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 Caïazzo, Hélène Verkindt, B. L. Legendre, Violeta Raverdy, Lydie Cheval, Nicolas Paquot, Jacques Piette, Sylvie Legrand-Poels, Myriam Aouadi, François Pattou, Bart Staels, David Dombrowicz
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. GDF-15 is a cytokine regulating food intake and a potential therapeutic target for treating obesity. Here, the authors show that macrophage infiltration in adipose tissue increases GDF-15 during obesity and type 2 diabetes, and hepatocyte stress further increases its levels when developing MASH.