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 1

Aortic endothelial cells are enriched for Glp1r expression, and Tie2-directed recombination reduces Glp1r mRNA in multiple organs.

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Aortic endothelial cells are enriched for Glp1r expression, and Tie2-dir...
Isolated cells from mouse aortas were subjected to FACS cytometry collection. (A) Gating strategy. (B) Glp1r versus Ppia expression levels in whole heart atria (Atr) and whole aorta (Aor) as well as FACS-collected cells that are endothelial cells (CD31+), immune cells (CD45+), or remaining cell types (CD31–/CD45–) from either chow-fed WT mice or Ldlr–/– mice fed HFHC diet for 18 weeks. For whole tissue, n = 5. FACS-derived cells were isolated from aortas pooled from 5 to 9 mice to generate n = 3–5 independent pooled samples for analysis. (C) Glp1r expression was analyzed in tissues from Glp1rTie2+/+ and Glp1rTie2–/– mice and is depicted relative to Ppia mRNA transcripts in whole aorta, spleen (Spl), liver (Liv), bone marrow, PBMCs, and lung (Lng) (left). For pancreas and lung, relative Glp1r mRNA was normalized to levels of Rpl32 (right) (n = 6–9). (D) Gut sections from the jejunum (Jej) and samples enriched for gut IELs were assessed for Glp1r versus Ppia expression and IEL markers Itgae and Cd3g to confirm successful IEL purification (n = 5–8). Data are presented as mean ± SD, with individual data points shown. *P < 0.05, Student’s t test for effect of Glp1rTie2+/+ versus Glp1rTie2–/– genotype.