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Open Access 01-12-2023 | Dyslipidemia | Research

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

Authors: Stephan Sachs, Anna Götz, Brian Finan, Annette Feuchtinger, Richard D. DiMarchi, Yvonne Döring, Christian Weber, Matthias H. Tschöp, Timo D. Müller, Susanna M. Hofmann

Published in: Cardiovascular Diabetology | Issue 1/2023

Abstract

Background

Agonism 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.

Methods

After 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.

Results

Herein 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.

Conclusions

This 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.

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Title: GIP receptor agonism improves dyslipidemia and atherosclerosis independently of body weight loss in preclinical mouse model for cardio-metabolic disease
Authors: Stephan Sachs
Anna Götz
Brian Finan
Annette Feuchtinger
Richard D. DiMarchi
Yvonne Döring
Christian Weber
Matthias H. Tschöp
Timo D. Müller
Susanna M. Hofmann
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Dyslipidemia
Arterial Occlusive Disease
Obesity
Obesity
Published in: Cardiovascular Diabetology / Issue 1/2023
Electronic ISSN: 1475-2840
DOI: https://doi.org/10.1186/s12933-023-01940-2

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Abstract

Background

Methods

Results

Conclusions

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