Insulin Sensitivity Is Retained in Mice with Endothelial Loss of Carcinoembryonic Antigen Cell Adhesion Molecule 1.

Harrison T Muturi,Abraham D Lee,Hyelim Noh,Emily L Esakov,Sonia M Najjar,Marcia F Mcinerney,Saja S Khuder,Hilda E Ghadieh,Heejoon Kang,Jason K Kim

doi:10.3390/cells10082093

Abstract

CEACAM1 regulates endothelial barrier integrity. Because insulin signaling in extrahepatic target tissues is regulated by insulin transport through the endothelium, we aimed at investigating the metabolic role of endothelial CEACAM1. To this end, we generated endothelial cell-specific Ceacam1 null mice (VECadCre+Cc1fl/fl) and carried out their metabolic phenotyping and mechanistic analysis by comparison to littermate controls. Hyperinsulinemic-euglycemic clamp analysis showed intact insulin sensitivity in VECadCre+Cc1fl/fl mice. This was associated with the absence of visceral obesity and lipolysis and normal levels of circulating non-esterified fatty acids, leptin, and adiponectin. Whereas the loss of endothelial Ceacam1 did not affect insulin-stimulated receptor phosphorylation, it reduced IRS-1/Akt/eNOS activation to lower nitric oxide production resulting from limited SHP2 sequestration. It also reduced Shc sequestration to activate NF-κB and increase the transcription of matrix metalloproteases, ultimately inducing plasma IL-6 and TNFα levels. Loss of endothelial Ceacam1 also induced the expression of the anti-inflammatory CEACAM1-4L variant in M2 macrophages in white adipose tissue. Together, this could cause endothelial barrier dysfunction and facilitate insulin transport, sustaining normal glucose homeostasis and retaining fat accumulation in adipocytes. The data assign a significant role for endothelial cell CEACAM1 in maintaining insulin sensitivity in peripheral extrahepatic target tissues.

Highlights

Carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) is a transmembrane glycoprotein that undergoes phosphorylation by insulin and vascular endothelial growth factor receptor-2 (VEGFR2) [1,2]
The endothelial layer lining the vasculature of skeletal muscle and adipose tissue is continuous and forms an endothelial barrier that regulates insulin transport to the interstitial space to bind to its receptors on myocytes [9] and adipocytes [10]
Normal insulin metabolism in VECadherin+Cc1fl/fl mice is consistent with: (1) the rapid and passive transport of secreted insulin from the portal vein to hepatocytes through fenestrae in the liver endothelium to be targeted to degradation, (2) intact CEACAM1 in hepatocytes, main sites of insulin extraction and (3) insulin is not significantly degraded in endothelial cells [11]

Summary

Introduction

Carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) is a transmembrane glycoprotein that undergoes phosphorylation by insulin and vascular endothelial growth factor receptor-2 (VEGFR2) [1,2]. It is highly expressed in hepatocytes, where it promotes insulin clearance to sustain insulin sensitivity [3]. This is mediated by partaking in the insulin receptor internalization complex and increasing the rate of its cellular uptake. Receptor-mediated insulin transport in endothelial cells appears to be vastly in caveolae [12], where CEACAM1 has recently been found to bind to caveolin-1 [13]

Methods

Discussion

Conclusion