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

Diabetes. 2016 Apr;65(4):861-73. doi: 10.2337/db15-1231. Epub 2016 Jan 28.


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 γ coactivator 1α (PGC-1α) together with estrogen-related receptor α (ERR-α) regulates expression of Vegfb Mice overexpressing PGC-1α under the muscle creatine kinase promoter (MPGC-1αTG mice) displayed increased Vegfb expression, and this was accompanied by increased muscular lipid accumulation. Ablation of Vegfb in MPGC-1αTG 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-1α overexpression and the development of the diabetes-like phenotype in HFD-fed MPGC-1αTG mice. The findings identify Vegfb as a novel gene regulated by the PGC-1α/ERR-α signaling pathway. Furthermore, the study highlights the role of PGC-1α 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.

MeSH terms

  • Animals
  • COS Cells
  • Cell Respiration / genetics
  • Cells, Cultured
  • Chlorocebus aethiops
  • Fatty Acids / metabolism*
  • Gene Expression Regulation
  • Male
  • Mice
  • Mice, Transgenic
  • Mitochondria, Muscle / metabolism*
  • Muscle, Skeletal / metabolism*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / physiology*
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor B / genetics*


  • Fatty Acids
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor B
  • vascular endothelial growth factor A, mouse
  • vascular endothelial growth factor B, mouse