Adipose Tissue VEGF‐D Overexpression Increases Lymphatic Vessel Density and Protects Against Inflammation and Insulin Resistance in Obesity

• Published in: The FASEB journal Vol. 31; no. S1
• Main Authors: Lammoglia, Gabriela M, Barajas, Sheridan E, Reyna, Andrea J, Rutkowski, Joseph M
• Format: Journal Article
• Language: English
• Published: 01-04-2017
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.31.1_supplement.683.3

Abstract only
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 receptor‐3 (VEGFR‐3) signaling. We took advantage of the unique binding of murine VEGF‐D to VEGFR‐3 and generated mice capable of inducible, tissue‐specific expression of murine VEGF‐D under a tightly‐controlled tetracycline response element (TRE) promoter to stimulate lymphangiogenesis. Crossed with adipocyte‐specific adiponectin‐rtTA mice (Adipo‐VD), VEGF‐D 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, VEGF‐D 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, VEGF‐D 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, Adipo‐VD gained equivalent weight and adiposity as littermate controls, but were markedly more insulin sensitive. White adipose tissues in Adipo‐VD mice were full of lymphatics, but exhibited less fibrosis, contained fewer crown‐like structure macrophages, and displayed increased UCP‐1 RNA and protein. Infusion of CD45.1+ leukocytes into CD45.2+ Adipo‐VD mice identified fewer immune cells accumulating in the Adipo‐VD 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 VEGFR‐3 signaling as a potential target in the metabolic syndrome.