Adipose Tissue VEGF-D Overexpression Increases Lymphatic Vessel Density and Protects Against Inflammation and Insulin Resistance in Obesity Conference Paper uri icon

abstract

  • Lymphatic vessels modulate tissue fluid balance and inflammation and provide a conduit for endocrine and lipid transport: all mechanisms that could potentially regulate adipose tissue physiology in obesity. The growth of new lymphatic vessels in is mediated through vascular endothelial growth factor receptor3 (VEGFR3) signaling. We took advantage of the unique binding of murine VEGFD to VEGFR3 and generated mice capable of inducible, tissuespecific expression of murine VEGFD under a tightlycontrolled tetracycline response element (TRE) promoter to stimulate lymphangiogenesis. Crossed with adipocytespecific adiponectinrtTA mice (AdipoVD), VEGFD overexpression by adipocytes induced de novo lymphangiogenesis in murine white adipose tissue and a massive expansion of brown adipose tissue lymphatics. Upon removal of the doxycycline stimulus, VEGFD expression returned to normal and the expanded adipose tissue lymphatics regressed. The new white adipose lymphatic network provided a route for increased glycerol flux during lipolysis. As a chemokine, VEGFD expression recruited macrophages and caused fibrosis in white adipose tissue on chow diet, but no negative systemic metabolic consequences were identified. On high fat diet feeding, AdipoVD gained equivalent weight and adiposity as littermate controls, but were markedly more insulin sensitive. White adipose tissues in AdipoVD mice were full of lymphatics, but exhibited less fibrosis, contained fewer crownlike structure macrophages, and displayed increased UCP1 RNA and protein. Infusion of CD45.1+ leukocytes into CD45.2+ AdipoVD mice identified fewer immune cells accumulating in the AdipoVD subcutaneous adipose with more trafficking out and into the inguinal lymph node. The increased lymphatic density thus reduces local inflammation in adipose tissue, manifesting as decreased liver triglyceride, increased insulin sensitivity, and overall healthier obesity highlighting the roles of lymphatic in regulating inflammatory pathologies and VEGFR3 signaling as a potential target in the metabolic syndrome.

published proceedings

  • FASEB JOURNAL

author list (cited authors)

  • Lammoglia, G. M., Barajas, S. E., Reyna, A. J., & Rutkowski, J. M.

complete list of authors

  • Lammoglia, Gabriela M||Barajas, Sheridan E||Reyna, Andrea J||Rutkowski, Joseph M

publisher