GIP receptor agonism improves dyslipidemia and atherosclerosis independently of body weight loss in preclinical mouse model for cardio-metabolic disease

Cardiovascular Diabetology

Research

Yvonne Döring¹  Richard D. DiMarchi²  Christian Weber³  Timo D. Müller⁴  Matthias H. Tschöp⁵  Susanna M. Hofmann⁶  Anna Götz⁷  Stephan Sachs⁸  Brian Finan⁹  Annette Feuchtinger^1,10 

[1] Department of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland;Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich, Germany;DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany;Department of Chemistry, Indiana University, Bloomington, IN, USA;Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich, Germany;DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany;Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands;Munich Cluster for Systems Neurology (SyNergy), Munich, Germany;Institute for Diabetes and Obesity, Division of Metabolic Diseases, Helmholtz Diabetes Center at Helmholtz Centre Munich, Munich, Germany;German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany;Institute for Diabetes and Obesity, Division of Metabolic Diseases, Helmholtz Diabetes Center at Helmholtz Centre Munich, Munich, Germany;Technische Universität München, 80333, Munich, Germany;German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany;Institute for Diabetes and Regeneration, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764, Neuherberg, Germany;German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany;Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany;Institute for Diabetes and Regeneration, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764, Neuherberg, Germany;Institute for Diabetes and Obesity, Division of Metabolic Diseases, Helmholtz Diabetes Center at Helmholtz Centre Munich, Munich, Germany;Institute for Diabetes and Regeneration, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764, Neuherberg, Germany;Institute for Diabetes and Obesity, Division of Metabolic Diseases, Helmholtz Diabetes Center at Helmholtz Centre Munich, Munich, Germany;Technische Universität München, 80333, Munich, Germany;Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA;Research Unit Analytical Pathology, Helmholtz Center Munich, 85764, Neuherberg, Germany;

关键词: GIP agonist;    acyl-GIP;    Obesity;    Dyslipidemia;    Atherosclerosis;    Cardiometabolic disease;    Mice;   

DOI  :  10.1186/s12933-023-01940-2

 received in 2023-05-09, accepted in 2023-07-24,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundAgonism at the receptor for the glucose-dependent insulinotropic polypeptide (GIPR) is a key component of the novel unimolecular GIPR:GLP-1R co-agonists, which are among the most promising drugs in clinical development for the treatment of obesity and type 2 diabetes. The therapeutic effect of chronic GIPR agonism to treat dyslipidemia and thus to reduce the cardiovascular disease risk independently of body weight loss has not been explored yet.MethodsAfter 8 weeks on western diet, LDL receptor knockout (LDLR-/-) male mice were treated with daily subcutaneous injections of long-acting acylated GIP analog (acyl-GIP; 10nmol/kg body weight) for 28 days. Body weight, food intake, whole-body composition were monitored throughout the study. Fasting blood glucose and intraperitoneal glucose tolerance test (ipGTT) were determined on day 21 of the study. Circulating lipid levels, lipoprotein profiles and atherosclerotic lesion size was assessed at the end of the study. Acyl-GIP effects on fat depots were determined by histology and transcriptomics.ResultsHerein we found that treatment with acyl-GIP reduced dyslipidemia and atherogenesis in male LDLR-/- mice. Acyl-GIP administration resulted in smaller adipocytes within the inguinal fat depot and RNAseq analysis of the latter revealed that acyl-GIP may improve dyslipidemia by directly modulating lipid metabolism in this fat depot.ConclusionsThis study identified an unanticipated efficacy of chronic GIPR agonism to improve dyslipidemia and cardiovascular disease independently of body weight loss, indicating that treatment with acyl-GIP may be a novel approach to alleviate cardiometabolic disease.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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