Map4k4 impairs energy metabolism in endothelial cells and promotes insulin resistance in obesity

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 postdevelopment. 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.

Insulin resistance disrupts cell integrity, mitochondrial function, and inflammatory signaling in lymphatic endothelium

“…Primary ECs that were a mixture of lymphatic and blood ECs showed enhanced glycolytic and mitochondrial respiration in the absence of MAP4K4. However, specific signaling mechanisms and metabolic effects in the blood and lymphatic endothelium that may be contributing to the observed effects were not delineated . In this study, we have shown that while insulin resistance promotes mitochondrial dysfunction in LECs (Figure E,F), glycolytic capacity (Figure G) is not altered, suggesting that LECs may utilize mitochondria as a predominant energy source.…”

“…Wong et al had shown that fatty acid β‐oxidation was higher in LECs than in arterial, venous, and microvascular BECs, whereas glycolytic flux was lower, suggesting the important role of mitochondrial oxidation in LEC metabolism. Studies have also shown that Map4k4 impairs energy metabolism in ECs and promotes insulin resistance during high‐fat diet‐induced obesity and its systemic loss improves insulin sensitivity . Primary ECs that were a mixture of lymphatic and blood ECs showed enhanced glycolytic and mitochondrial respiration in the absence of MAP4K4.…”

Capillary Rarefaction in Obesity and Metabolic Diseases—Organ-Specificity and Possible Mechanisms

“…Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is a serine/threonine kinase that activates the mitogen-activated protein kinase 8 (MAPK8)/c-Jun N-terminal kinase (JNK) pathway and it is suggested to also play a role in TNF-α signaling. EC-specific Map4k4 knockout ( M4k4 iECKO ) mice displayed a trend towards improved glucose tolerance and significantly enhanced insulin sensitivity compared to controls after a 16-week-long HFD feeding [ 114 ]. When the capillary densities were assessed, the authors found that eWAT capillary densities were comparable between M4k4 iECKO mice and the control littermates under both normal chow and HFD.…”

“…When the capillary densities were assessed, the authors found that eWAT capillary densities were comparable between M4k4 iECKO mice and the control littermates under both normal chow and HFD. Interestingly, the skeletal muscle of M4k4 iECKO mice did not undergo capillary rarefaction during 16 weeks of HFD and the ECs isolated from these mice displayed enhanced energy metabolism and resistance to senescence, which could explain why these mice were more sensitive to insulin after HFD [ 114 ]. Despite this metabolic improvement, M4k4 iECKO mice also displayed lymphatic vascular defects, as noted by chyle leakage in the abdomen (chylous ascites) and increased immune cell content in eWAT.…”

Vascular Endothelial Regulation of Obesity-Associated Insulin Resistance

“…A study found that the capillary endothelial fatty acid binding proteins 4 and 5 (FABP4/5) are required for fatty acid uptake in heart and skeletal muscle, organs that possess muscle-type continuous capillary ( 89 ). In contrast, the function of an EC-derive mitogen activated protein kinase kinase kinase kinase 4 (MAP4K4) has opposing functions in blood and lymphatic ECs: while MAP4K4 is required for lymphatic vascular integrity, blood EC-MAP4K4 induces insulin resistance by impairing vascular function in obesity ( 90 ).…”