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

  • Cardiovasc Diabetol. 2023 Aug 17;22(1):217. doi: 10.1186/s12933-023-01940-2.
Stephan Sachs  #  1  2  3 ,  Anna Götz  #  1  2 ,  Brian Finan  4 ,  Annette Feuchtinger  5 ,  Richard D DiMarchi  6 ,  Yvonne Döring  7  8  9 ,  Christian Weber  8  9  10  11 ,  Matthias H Tschöp  2  3  12 ,  Timo D Müller  13  14 ,  Susanna M Hofmann  15  16  17
Affiliations
  • 1. Institute for Diabetes and Regeneration, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764, Neuherberg, Germany.
  • 2. Institute for Diabetes and Obesity, Division of Metabolic Diseases, Helmholtz Diabetes Center at Helmholtz Centre Munich, Munich, Germany.
  • 3. Technische Universität München, 80333, Munich, Germany.
  • 4. Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA.
  • 5. Research Unit Analytical Pathology, Helmholtz Center Munich, 85764, Neuherberg, Germany.
  • 6. Department of Chemistry, Indiana University, Bloomington, IN, USA.
  • 7. Department of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • 8. Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich, Germany.
  • 9. DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
  • 10. Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
  • 11. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
  • 12. German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany.
  • 13. Institute for Diabetes and Obesity, Division of Metabolic Diseases, Helmholtz Diabetes Center at Helmholtz Centre Munich, Munich, Germany. [email protected].
  • 14. German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany. [email protected].
  • 15. Institute for Diabetes and Regeneration, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764, Neuherberg, Germany. [email protected].
  • 16. German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany. [email protected].
  • 17. Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany. [email protected].
  • # Contributed equally.
PMID: 37592302 DOI: 10.1186/s12933-023-01940-2
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.

Keywords
Atherosclerosis; Cardiometabolic disease; Dyslipidemia; GIP agonist; Mice; Obesity; acyl-GIP.
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