Inducible Adipose Tissue VEGF‐D Drives Lymphatic Expansion and Improves Systemic Insulin Sensitivity in Obesity

Abstract

The metabolic syndrome etiology finds its roots in inflammatory adipose tissue expansion. Rapid adipose expansion, adipocyte insulin resistance, and tissue hypoxia result in dysregulated lipolysis and immune cell infiltration. Increased circulating cytokines and elevated lipid levels lead to ectopic lipid deposition and systemic insulin resistance. Lymphatic vessels regulate inflammation by clearing fluid, cytokines, antigens, and immune cells from the site of inflammation. We hypothesized that increased lymphatic vessel density in adipose tissue may ameliorate local inflammation and thus protect against the metabolic system in obesity. We generated transgenic 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 and brown adipose tissues. Adipo‐VD mice gained equivalent weight on high fat diet feeding to their littermates, but demonstrated improved insulin sensitivity and elevated adipose metabolism. b‐adrenergic stimulation of Adipo‐VD mice white adipose lymphatic network promoted enhanced lipolysis and postulated a new route for increased glycerol flux into the circulation: lymphatic vessels. Beyond the increased lymphatic vasculature, adipose tissue architecture and adipocyte size were the same. While chemokine levels in the tissues were unchanged, we quantified fewer macrophage crown‐like structures and reduced macrophages and Tcells in the tissue. Quantitation of infused CD45.1+ leukocytes population in the CD45.2+ Adipo‐VD subcutaneous adipose tissue also indicated increased trafficking to the inguinal lymph node. Increased adipose tissue lymphatic density thus increases insulin sensitivity and enhances immune cell flux from expanded adipose tissue making lymphatics a novel target in the metabolic syndrome.Support or Funding InformationLipedema FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.