Endothelial PDGF-CC regulates angiogenesis-dependent thermogenesis in beige fat

Abstract

Cold- and β3-adrenoceptor agonist-induced sympathetic activation leads to angiogenesis and UCP1-dependent thermogenesis in mouse brown and white adipose tissues. Here we show that endothelial production of PDGF-CC during white adipose tissue (WAT) angiogenesis regulates WAT browning. We find that genetic deletion of endothelial VEGFR2, knockout of the Pdgf-c gene or pharmacological blockade of PDGFR-α impair the WAT-beige transition. We further show that PDGF-CC stimulation upregulates UCP1 expression and acquisition of a beige phenotype in differentiated mouse WAT-PDGFR-α+ progenitor cells, as well as in human WAT-PDGFR-α+ adipocytes, supporting the physiological relevance of our findings. Our data reveal a paracrine mechanism by which angiogenic endothelial cells modulate adipocyte metabolism, which may provide new targets for the treatment of obesity and related metabolic diseases.

Adipocyte ADRB3 Down-Regulated in Chinese Overweight Individuals Adipocyte ADRB3 in Overweight

“…Exposure to the cold [16-18] or selective ADRB3 agonists [7] resulted in higher resting metabolic rate and hBAT activity in healthy individuals as measured via 18 F-FDG/PET-CT, in whom the ADRB3 pathway was considered as a dominant signaling pathway to promote the activation or differentiation of beige adipocytes [17, 19, 20]. ADRB3 belong to G protein-coupled receptors and are abundant in adipose tissue, especially in the BAT [17, 21].…”

Brown and Beige Adipose Tissues in Health and Disease

“…Cold exposure or β adrenergic agonist stimulation induces angiogenesis in both WAT and BAT (277, 346), facilitating fuel delivery, heat dissipation, and thermogenesis. VEGF-A is a key angiogenic growth factor, and overexpression of VEGF-A either in all adipocytes or in UCP1 + brown and beige adipocytes increases adipose vascularization, beige adipogenesis, and BAT and beige fat thermogenesis in mice (73, 293, 294).…”

“…VEGF-A is a key angiogenic growth factor, and overexpression of VEGF-A either in all adipocytes or in UCP1 + brown and beige adipocytes increases adipose vascularization, beige adipogenesis, and BAT and beige fat thermogenesis in mice (73, 293, 294). Conversely, inhibition of adipose angiogenesis by deleting endothelial VEGFR2 impairs β adrenergic-stimulated beige adipogenesis and nonshivering thermogenesis (277, 346). A reduction in vascularization and blood flow is expected to induce hypoxia and activation of HIF1α, and adipocyte-specific ablation of HIF1α or its binding partner ARNT increases energy expenditure in mice (141, 163), suggesting that the hypoxia-HIF1α axis suppresses the recruitments and activities of BAT and/or beige fat.…”

“…PDGF-CC is able to stimulate both PDGFRα homodimers and PDGFα/β heterodimers, and it also stimulates differentiation of PDGFRα + progenitors into beige adipocytes (277). In line with this finding, deletion of PDGF-C , or pharmacological blockage of PDGFRα or PDGRβ, inhibits β adrenergic-stimulated beige adipogenesis in mice (277).…”

“…PDGF-CC is able to stimulate both PDGFRα homodimers and PDGFα/β heterodimers, and it also stimulates differentiation of PDGFRα + progenitors into beige adipocytes (277). In line with this finding, deletion of PDGF-C , or pharmacological blockage of PDGFRα or PDGRβ, inhibits β adrenergic-stimulated beige adipogenesis in mice (277). However, activation of PDGFRα signaling was also reported to stimulate differentiation of adipose mesenchymal progenitors into fibrotic cells at the expense of suppressing adipogenesis (138).…”