UMMS Affiliation

Program in Molecular Medicine; UMass Metabolic Network

Date

6-13-2017

Document Type

Article Postprint

Disciplines

Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology

Abstract

The blood vasculature responds to insulin, influencing hemodynamic changes in the periphery, which promotes tissue nutrient and oxygen delivery and thus metabolic function. The lymphatic vasculature regulates fluid and lipid homeostasis, and impaired lymphatic function can contribute to atherosclerosis and obesity. Recent studies have suggested a role for endothelial cell (EC) Mitogen activated protein kinase kinase kinase kinase 4 (Map4k4) in developmental angiogenesis and lymphangiogenesis as well as atherosclerosis. Here, we show that inducible EC Map4k4 deletion in adult mice ameliorates metabolic dysfunction in obesity despite the development of chylous ascites and a concomitant striking increase in adipose tissue lymphocyte content. Despite these defects, animals lacking endothelial Map4k4 were protected from skeletal muscle microvascular rarefaction in obesity, and primary ECs lacking Map4k4 displayed reduced senescence and increased metabolic capacity. Thus, endothelial Map4k4 has complex and opposing functions in the blood and lymphatic endothelium post-development. Whereas blood endothelial Map4k4 promotes vascular dysfunction and impairs glucose homeostasis in adult animals, lymphatic endothelial Map4k4 is required to maintain lymphatic vascular integrity and regulate immune cell trafficking in obesity.

Rights and Permissions

Authors' accepted peer-reviewed manuscript posted after 12 months as allowed by the publisher's author rights policy at http://www.the-aps.org/mm/Publications/Info-For-Authors/Copyright. Citation: Am J Physiol Endocrinol Metab. 2017 Jun 13:ajpendo.00037.2017. doi: 10.1152/ajpendo.00037.2017. [Epub ahead of print] Link to article on publisher's site

Related Resources

Link to Article in PubMed

Keywords

Endothelial, MAP4K4, inflammation, lymphatic, obesity

PubMed ID

28611026

Available for download on Wednesday, June 13, 2018

Share

COinS