Program in Molecular Medicine; Department of Medicine, Division of Endocrinology, Metabolism and Diabetes
Amino Acids, Peptides, and Proteins | Cell Biology | Endocrinology | Endocrinology, Diabetes, and Metabolism | Hormones, Hormone Substitutes, and Hormone Antagonists
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.
carcinoembryonic antigen-related cell adhesion molecule-1, insulin clearance, insulin resistance, insulin transport, normo-insulinemia
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DOI of Published Version
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
Muturi HT, Khuder SS, Ghadieh HE, Esakov EL, Noh HL, Kang H, McInerney MF, Kim JK, Lee AD, Najjar SM. (2021). Insulin Sensitivity Is Retained in Mice with Endothelial Loss of Carcinoembryonic Antigen Cell Adhesion Molecule 1. Open Access Publications by UMass Chan Authors. https://doi.org/10.3390/cells10082093. Retrieved from https://escholarship.umassmed.edu/oapubs/4877
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