UMMS Affiliation

Program in Molecular Medicine; Department of Medicine, Division of Endocrinology, Metabolism and Diabetes

Publication Date

2021-08-14

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Cell Biology | Endocrinology | Endocrinology, Diabetes, and Metabolism | Hormones, Hormone Substitutes, and Hormone Antagonists

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+Cc1(fl/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+Cc1(fl/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-kappaB and increase the transcription of matrix metalloproteases, ultimately inducing plasma IL-6 and TNFalpha 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.

Keywords

carcinoembryonic antigen-related cell adhesion molecule-1, insulin clearance, insulin resistance, insulin transport, normo-insulinemia

Rights and Permissions

Copyright © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

DOI of Published Version

10.3390/cells10082093

Source

Muturi HT, Khuder SS, Ghadieh HE, Esakov EL, Noh H, Kang H, McInerney MF, Kim JK, Lee AD, Najjar SM. Insulin Sensitivity Is Retained in Mice with Endothelial Loss of Carcinoembryonic Antigen Cell Adhesion Molecule 1. Cells. 2021 Aug 14;10(8):2093. doi: 10.3390/cells10082093. PMID: 34440862; PMCID: PMC8394790. Link to article on publisher's site

Journal/Book/Conference Title

Cells

Related Resources

Link to Article in PubMed

PubMed ID

34440862

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

Share

COinS