Differential importance of endothelial and hematopoietic cell GLP-1Rs for cardiometabolic versus hepatic actions of semaglutide
Brent A. McLean, Chi Kin Wong, Kiran Deep Kaur, Randy J. Seeley, Daniel J. Drucker
Brent A. McLean, Chi Kin Wong, Kiran Deep Kaur, Randy J. Seeley, Daniel J. Drucker
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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.