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

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RA) 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 the 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 Glp1r Tie2-/-mice. The GLP-1RA semaglutide reduced the development of atherosclerosis induced by viral PCSK9 expression in both Glp1r Tie2+/+ and Glp1r Tie2-/-mice. Hepatic Glp1r mRNA transcripts were reduced in Glp1r Tie2-/-mice and liver Glp1r expression was localized to  T cells. Moreover, semaglutide reduced hepatic Tnf, Abcg1, Tgfb1, Cd3g, Ccl2, and Il2 expression, triglyceride content and collagen accumulation in high fat high cholesterol (HFHC) diet-fed Glp1r Tie2+/+ but not Glp1r Tie2-/-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 anti-inflammatory actions of semaglutide in the liver.

The anti-inflammatory feature of glucagon-like peptide-1 and its based diabetes drugs—Therapeutic potential exploration in lung injury

“…Recent observations made by McLean et al. 123 also indicated that functions of GLP-1RAs in extra-pancreatic organs could be attributed to GLP-1R expressed in endothelial and hematopoietic cell lineages, in agreement with the detection of GLP-1R in smooth muscle cells in the walls of arteries and arterioles of monkey and human lungs 118 .…”

“…Thus, it remains to be determined whether GLP-1RAs exert their anti-inflammatory and immune-modulatory functions via indirect mechanisms. This could involve a brain–peripheral tissue axis, or via interaction with a small population of immune cells, such as intestinal intraepithelial lymphocytes (IEL) or certain T lymphocytes ( γδ cells) 123 , 182 . Recent observations made by McLean et al.…”

“…Those mice exhibited reduced levels of Glp1r mRNA transcripts in aorta, liver, spleen, blood, and gut. Importantly, they have located liver Glp1r expression to γδ T lymphocytes while semaglutide mediated hepatic metabolic beneficial effects were observed in high fat diet challenged Glp1r Tie2+/+ mice but not in Glp1r Tie2−/ – mice 123 . Hence, they have suggested that observed in vivo functions of GLP-1-based drugs in certain extra-pancreatic organs could be attributed to endothelial and hematopoietic-cell expressed GLP-1R 123 .…”

“…Very recently, McLean et al. 123 conducted their investigation on potential murine Glp1r expression within endothelial and hematopoietic cells. They have created a mouse line with targeted inactivation of Glp1r in Tie2 + cells.…”

An Effective Glucagon-Like Peptide-1 Receptor Agonists, Semaglutide, Improves Sarcopenic Obesity in Obese Mice by Modulating Skeletal Muscle Metabolism

“…Glucagon-like peptide-1 (GLP-1) is a gut-derived incretin hormone that inhibits glucagon secretion and can lead to weight loss with prolonged use. 8 , 9 These mechanisms of action support the clinical development of anti-degradative glucagon-like peptide-1 receptor agonists (GLP-1RA) for the obesity, which was associated with type 2 diabetes mellitus, non-alcoholic fatty liver disease, and cardiovascular disease. 10 , 11 Although there is evidence that GLP-1RA can reduce body weight, however, this weight loss may not be entirely attributable to fat mass, estimated to be approximately 25–33% including a reduction in lean body mass (LBM).…”