title: PGC-1α Coordinates Mitochondrial Respiratory Capacity and Muscular Fatty Acid Uptake via Regulation of VEGF-B.
abstract: 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.
authors.affiliation: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Mehlem
authors.affiliation: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Isolde
authors.initials: I
authors.lastname: Palombo
authors.affiliation: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Xun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Carolina E
authors.initials: CE
authors.lastname: Hagberg
authors.affiliation: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden annelie.falkevall@ki.se ulf.pe.eriksson@ki.se.
authors.forename: Ulf
authors.initials: U
authors.lastname: Eriksson
authors.affiliation: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden annelie.falkevall@ki.se ulf.pe.eriksson@ki.se.
authors.forename: Annelie
authors.initials: A
authors.lastname: Falkevall
mesh_terms: D000818:Animals; D019556:COS Cells; D019069:Cell Respiration / Q000235:genetics; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D042561:Vascular Endothelial Growth Factor B / Q000235:genetics*
chemical_list: D005227:Fatty Acids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D042461:Vascular Endothelial Growth Factor A; D042561:Vascular Endothelial Growth Factor B; C467480:vascular endothelial growth factor A, mouse; C467482:vascular endothelial growth factor B, mouse