PGC-1α Coordinates Mitochondrial Respiratory Capacity and Muscular Fatty Acid Uptake via Regulation of VEGF-B

Vascular endothelial growth factor (VEGF) B belongs to the VEGF family, but in contrast to VEGF-A, VEGF-B does not regulate blood vessel growth. Instead, VEGF-B controls endothelial fatty acid (FA) uptake and was identified as a target for the treatment of type 2 diabetes. The regulatory mechanisms controlling Vegfb expression have remained unidentified. We show that peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) together with estrogen-related receptor a (ERR-a) regulates expression of Vegfb. Mice overexpressing PGC-1 alpha under the muscle creatine kinase promoter (MPGC-1 alpha TG mice) displayed increased Vegfb expression, and this was accompanied by increased muscular lipid accumulation. Ablation of Vegfb in MPGC-1 alpha TG mice fed a high fat diet (HFD) normalized glucose intolerance, insulin resistance, and dyslipidemia. We suggest that VEGF-B is the missing link between PGC-1 alpha overexpression and the development of the diabetes-like phenotype in HFD-fed MPGC-1 alpha TG mice. The findings identify Vegfb as a novel gene regulated by the PGC-1 alpha/ERR-alpha signaling pathway. Furthermore, the study highlights the role of PGC-1 alpha as a master metabolic sensor that by regulating the expression levels of Vegfa and Vegfb coordinates blood vessel growth and FA uptake with mitochondrial FA oxidation.