期刊
MOLECULAR METABOLISM
卷 65, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.molmet.2022.101586
关键词
Glucose-dependant insulinotropic polypeptide receptor; Atherosclerosis; Inflammation; Incretin; Cholesterol; Blood vessel
资金
- CIHR Foundation Grant [154321]
- Novo Nordisk Inc
- CanadaeIsrael Health Research Initiative - Canadian Institutes of Health Research
- CanadaeIsrael Health Research Initiative - Israel Science Foundation
- CanadaeIsrael Health Research Initiative - International Development Research Centre
- CanadaeIsrael Health Research Initiative - Azrieli Foundation
- Banting and Best Diabetes Centre-Novo Nordisk Chair in Incretin biology
- Novo Nordisk Foundation-Sinai Health Fund in Incretin biology
The loss of GIPR signaling in mice leads to increased aortic atherosclerosis and enhanced inflammation in the aorta and liver, despite reduced weight gain and preserved glucose homeostasis. These findings indicate that GIPR has a broader role in suppressing inflammation-related pathophysiology beyond its classical incretin role in metabolic control.
Objective: The gut hormone glucose-dependent insulinotropic polypeptide (GIP) stimulates beta cell function and improves glycemia through its incretin actions. GIP also regulates endothelial function and suppresses adipose tissue inflammation through control of macrophage activity. Activation of the GIP receptor (GIPR) attenuates experimental atherosclerosis and inflammation in mice, however whether loss of GIPR signaling impacts the development of atherosclerosis is uncertain. Methods: Atherosclerosis and related metabolic phenotypes were studied in Apoe(-/-):Gipr(-/-) mice and in Gipr(+/+) and Gipr(-/-) mice treated with an adeno-associated virus expressing PCSK9 (AAV-PCSK9). Bone marrow transplantation (BMT) studies were carried out using donor marrow from Apoe(-/-):Gipr(-/-)and Apoe(-/-):Gipr(+/+)mice transplanted into Apoe(-/-):Gipr(-/-) recipient mice. Experimental endpoints included the extent of aortic atherosclerosis and inflammation, body weight, glucose tolerance, and circulating lipid levels, the proportions and subsets of circulating leukocytes, and tissue gene expression profiles informing lipid and glucose metabolism, and inflammation. Results: Body weight was lower, circulating myeloid cells were reduced, and glucose tolerance was not different, however, aortic atherosclerosis was increased in Apoe(-/-):Gipr(-)/(-) mice and trended higher in Gipr(-/-) mice with atherosclerosis induced by AAV-PCSK9. Levels of mRNA transcripts for genes contributing to inflammation were increased in the aortae of Apoe(-/-):Gipr(-/-) mice and expression of a subset of inflammation-related hepatic genes were increased in Gipr(-/-) mice treated with AAV-PCSK9. BMT experiments did not reveal marked atherosclerosis, failing to implicate bone marrow derived GIPR thorn cells in the control of atherosclerosis or aortic inflammation. Conclusions: Loss of the Gipr in mice results in increased aortic atherosclerosis and enhanced inflammation in aorta and liver, despite reduced weight gain and preserved glucose homeostasis. These findings extend concepts of GIPR in the suppression of inflammation-related pathophysiology beyond its classical incretin role in the control of metabolism. (C) 2022 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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