title: VEGFB/VEGFR1-Induced Expansion of Adipose Vasculature Counteracts Obesity and Related Metabolic Complications.
abstract: Impaired angiogenesis has been implicated in adipose tissue dysfunction and the development of obesity and associated metabolic disorders. Here, we report the unexpected finding that vascular endothelial growth factor B (VEGFB) gene transduction into mice inhibits obesity-associated inflammation and improves metabolic health without changes in body weight or ectopic lipid deposition. Mechanistically, the binding of VEGFB to VEGF receptor 1 (VEGFR1, also known as Flt1) activated the VEGF/VEGFR2 pathway and increased capillary density, tissue perfusion, and insulin supply, signaling, and function in adipose tissue. Furthermore, endothelial Flt1 gene deletion enhanced the effect of VEGFB, activating the thermogenic program in subcutaneous adipose tissue, which increased the basal metabolic rate, thus preventing diet-induced obesity and related metabolic complications. In obese and insulin-resistant mice, Vegfb gene transfer, together with endothelial Flt1 gene deletion, induced weight loss and mitigated the metabolic complications, demonstrating the therapeutic potential of the VEGFB/VEGFR1 pathway.
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, 00290 Helsinki, Finland. Electronic address: marius.robciuc@helsinki.fi.
authors.forename: Marius R
authors.initials: MR
authors.lastname: Robciuc
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, 00290 Helsinki, Finland.
authors.forename: Riikka
authors.initials: R
authors.lastname: Kivelä
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Williams
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
authors.forename: Jan Freark
authors.initials: JF
authors.lastname: de Boer
authors.affiliation: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
authors.forename: Theo H
authors.initials: TH
authors.lastname: van Dijk
authors.affiliation: Oulu Center for Cell-Matrix Research and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Biocenter Oulu, 90220 Oulu, Finland.
authors.forename: Harri
authors.initials: H
authors.lastname: Elamaa
authors.affiliation: Department of Biosciences and Physiology and Neuroscience, University of Helsinki, Biocenter 3, 00790 Helsinki, Finland.
authors.forename: Feven
authors.initials: F
authors.lastname: Tigistu-Sahle
authors.affiliation: Biomedicum Imaging Unit, University of Helsinki, Biomedicum Helsinki, 00290 Helsinki, Finland.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Molotkov
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, 00290 Helsinki, Finland.
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Leppänen
authors.affiliation: Department of Biosciences and Physiology and Neuroscience, University of Helsinki, Biocenter 3, 00790 Helsinki, Finland.
authors.forename: Reijo
authors.initials: R
authors.lastname: Käkelä
authors.affiliation: Oulu Center for Cell-Matrix Research and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Biocenter Oulu, 90220 Oulu, Finland.
authors.forename: Lauri
authors.initials: L
authors.lastname: Eklund
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Wasserman
authors.affiliation: Department of Pediatrics, Center for Liver Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, 00290 Helsinki, Finland. Electronic address: kari.alitalo@helsinki.fi.
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
mesh_terms: D000273:Adipose Tissue / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D009765:Obesity / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D042561:Vascular Endothelial Growth Factor B / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D042561:Vascular Endothelial Growth Factor B; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2