Fumarate drives inflammatory crosstalk between adipocytes and macrophages to promote foam cell formation

Adipose tissue plays a central role in metabolic homeostasis, and its dysfunction caused by macrophage-mediated inflammation contributes to vascular disease. This study investigated the role of fumarate in adipocyte–macrophage interactions and its involvement in foam cell formation. Serum levels of S-(2-succinyl)cysteine, a marker of protein modification by fumarate, were elevated in individuals with atherosclerosis and in apolipoprotein E-deficient mice. To investigate the involvement of adipocyte–macrophage interactions in fumarate accumulation, adipocytes and macrophages were co-cultured. Fumarate production and S-(2-succinyl)cysteine formation were increased in co-cultures compared with monocultures. Increased fumarate production was accompanied by elevated expression of monocyte chemoattractant protein-1, tumor necrosis factor-alpha, and transforming growth factor-beta in macrophages. Tumor necrosis factor-alpha promoted fumarate secretion from adipocytes and induced accumulation of metabolic intermediates from glycolysis to the tricarboxylic acid cycle, together with reduced expression of tricarboxylic acid cycle enzymes. Furthermore, fumarate enhanced tumor necrosis factor-alpha production in macrophages and promoted lipid accumulation from low-density lipoprotein, resulting in foam cell formation. These findings provide evidence that fumarate mediates adipocyte–macrophage interactions, establishing a chronic inflammatory cycle that drives foam cell formation and atherogenesis.