VEGFB promotes adipose tissue thermogenesis by inhibiting norepinephrine clearance in macrophages

Adipokines play key roles in adaptive thermogenesis of beige adipocytes, though its detailed regulatory mechanisms are not fully understood. In the present study, we identify a critical function of vascular endothelial growth factor B (VEGFB)/vascular endothelial growth factor receptor 1 (VEGFR1) signaling in improving thermogenesis in white adipose tissue (WAT). In mouse subcutaneous WAT (scWAT), thermogenesis activation leads to the up-regulation of VEGFB in adipocytes and its receptor VEGFR1 in macrophages. Ablation of adipocyte VEGFB results in deficiency in murine WAT browning. Meanwhile, supplementation of VEGFB promotes WAT thermogenesis, but this effect is blocked by knockout of macrophage VEGFR1. Mechanistic studies show that the VEGFB-activated VEGFR1 inhibits p38 MAPK signaling through its dissociation with receptor for activated C kinase 1, thereby preventing norepinephrine transporter (solute carrier family 6 member 2) and norepinephrine-degrative monoamine oxidase a mediated norepinephrine clearance in macrophages. Our findings demonstrate that VEGFB/VEGFR1 circuit contributes to the WAT thermogenesis.