Differential importance of endothelial and hematopoietic cell GLP-1Rs for cardiometabolic versus hepatic actions of semaglutide
Brent A. McLean, … , Randy J. Seeley, Daniel J. Drucker
Brent A. McLean, … , Randy J. Seeley, Daniel J. Drucker
Published October 21, 2021
Citation Information: JCI Insight. 2021;6(22):e153732. https://doi.org/10.1172/jci.insight.153732.
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Research Article Endocrinology

Differential importance of endothelial and hematopoietic cell GLP-1Rs for cardiometabolic versus hepatic actions of semaglutide

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used to treat diabetes and obesity and reduce rates of major cardiovascular events, such as stroke and myocardial infarction. Nevertheless, the identity of GLP-1R–expressing cell types mediating the cardiovascular benefits of GLP-1RA remains incompletely characterized. Herein, we investigated the importance of murine Glp1r expression within endothelial and hematopoietic cells. Mice with targeted inactivation of Glp1r in Tie2+ cells exhibited reduced levels of Glp1r mRNA transcripts in aorta, liver, spleen, blood, and gut. Glp1r expression in bone marrow cells was very low and not further reduced in Glp1rTie2–/– mice. The GLP-1RA semaglutide reduced the development of atherosclerosis induced by viral PCSK9 expression in both Glp1rTie2+/+ and Glp1rTie2–/– mice. Hepatic Glp1r mRNA transcripts were reduced in Glp1rTie2–/– mice, and liver Glp1r expression was localized to γδ T cells. Moreover, semaglutide reduced hepatic Tnf, Abcg1, Tgfb1, Cd3g, Ccl2, and Il2 expression; triglyceride content; and collagen accumulation in high-fat, high-cholesterol diet–fed Glp1rTie2+/+ mice but not Glp1rTie2–/– mice. Collectively, these findings demonstrate that Tie2+ endothelial or hematopoietic cell GLP-1Rs are dispensable for the antiatherogenic actions of GLP-1RA, whereas Tie2-targeted GLP-1R+ cells are required for a subset of the antiinflammatory actions of semaglutide in the liver.

Authors

Brent A. McLean, Chi Kin Wong, Kiran Deep Kaur, Randy J. Seeley, Daniel J. Drucker

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Figure 3

Semaglutide attenuates glycemic excursion and levels of circulating cholesterol, triglycerides, and cytokines in Glp1rTie2+/+ and Glp1rTie2–/– mice.

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Semaglutide attenuates glycemic excursion and levels of circulating chol...
PCSK9-treated HFHC diet–fed mice were tested for blood glucose at weeks 12–13 of the 18-week PCSK9+HFHC diet protocol, with daily vehicle (Veh) or semaglutide (Sema; 10 μg/kg) administration. Mice were fasted for 5 hours followed by administration of 1.5 g/kg glucose for an oral glucose tolerance test (OGTT). (A) The area under the curve (AUC) was calculated to compare Veh with Sema treatment in Glp1rTie2+/+ and Glp1rTie2–/– mice. At weeks 16–17 of the treatment protocol, mice were fasted for 5 hours and blood was collected for fast protein lipid chromatography: (B) triglyceride and (C) cholesterol levels in VLDL, LDL,and HDL fractions were measured. (D) Cytokines were measured in plasma obtained from terminal bleeds at the end of the experiment (n = 6–14). Data are presented as mean ± SD, with individual data points shown. *P < 0.05 for Sema effect, 2-way ANOVA multiple-comparison test.