Oppositely biased glucagon-like peptide-1 receptor agonism does not differentially affect lipid metabolism in APOE*3-Leiden CETP mice
Author(s)
Type
Journal Article
Abstract
Aims
[D3,G40,K41.C16 diacid]exendin-4 (acyl-ExD3) and [F1,G40,K41.C16 diacid]exendin-4 (acyl-ExF1) are oppositely biased glucagon-like peptide-1 (GLP-1) receptor agonists that preferentially promote β-arrestin recruitment or G protein-induced signalling, respectively. The latter is more favourable in glycaemic control and induces a steeper reduction in body weight in diet-induced obese mice. Here, we compared the effects of G protein-biased agonist acyl-ExF1 to those of β-arrestin-biased agonist acyl-ExD3 on lipid metabolism in hyperlipidaemic mice.
Materials and methods
APOE*3-Leiden.CETP mice were treated with saline, acyl-ExD3 or acyl-ExF1 via intraperitoneal injections for 6 weeks or intracerebroventricular infusion for 18 days. Body weight and composition were monitored at regular intervals, as were plasma glucose, triglyceride and cholesterol levels. At endpoint, mice were injected with very low-density lipoprotein (VLDL)-like particles containing glycerol tri[3H]oleate to study triglyceride-derived fatty acid uptake by peripheral tissues including brown and white adipose tissue (BAT and WAT).
Results
Upon peripheral treatment, body weight gain was prevented and plasma glucose levels were reduced by acyl-ExF1, but circulating lipids were not affected by either acyl-ExF1 or acyl-ExD3. In contrast, central administration of either agonist strongly reduced plasma triglyceride and cholesterol levels, but did not affect glucose levels. Acyl-ExD3 and acyl-ExF1 increased [3H]oleate uptake by adipose tissue, reaching statistical significance for the uptake by BAT and WAT, respectively, compared to vehicle treatment.
Conclusion
The oppositely biased GLP-1 receptor agonists acyl-ExD3 and acyl-ExF1 do not differentially affect lipid metabolism in APOE*3-Leiden.CETP mice, while effects on glucose homeostasis and prevention of body weight gain are more pronounced upon peripheral acyl-ExF1 treatment.
[D3,G40,K41.C16 diacid]exendin-4 (acyl-ExD3) and [F1,G40,K41.C16 diacid]exendin-4 (acyl-ExF1) are oppositely biased glucagon-like peptide-1 (GLP-1) receptor agonists that preferentially promote β-arrestin recruitment or G protein-induced signalling, respectively. The latter is more favourable in glycaemic control and induces a steeper reduction in body weight in diet-induced obese mice. Here, we compared the effects of G protein-biased agonist acyl-ExF1 to those of β-arrestin-biased agonist acyl-ExD3 on lipid metabolism in hyperlipidaemic mice.
Materials and methods
APOE*3-Leiden.CETP mice were treated with saline, acyl-ExD3 or acyl-ExF1 via intraperitoneal injections for 6 weeks or intracerebroventricular infusion for 18 days. Body weight and composition were monitored at regular intervals, as were plasma glucose, triglyceride and cholesterol levels. At endpoint, mice were injected with very low-density lipoprotein (VLDL)-like particles containing glycerol tri[3H]oleate to study triglyceride-derived fatty acid uptake by peripheral tissues including brown and white adipose tissue (BAT and WAT).
Results
Upon peripheral treatment, body weight gain was prevented and plasma glucose levels were reduced by acyl-ExF1, but circulating lipids were not affected by either acyl-ExF1 or acyl-ExD3. In contrast, central administration of either agonist strongly reduced plasma triglyceride and cholesterol levels, but did not affect glucose levels. Acyl-ExD3 and acyl-ExF1 increased [3H]oleate uptake by adipose tissue, reaching statistical significance for the uptake by BAT and WAT, respectively, compared to vehicle treatment.
Conclusion
The oppositely biased GLP-1 receptor agonists acyl-ExD3 and acyl-ExF1 do not differentially affect lipid metabolism in APOE*3-Leiden.CETP mice, while effects on glucose homeostasis and prevention of body weight gain are more pronounced upon peripheral acyl-ExF1 treatment.
Date Issued
2025-06-01
Date Acceptance
2025-03-21
Citation
Diabetes, Obesity and Metabolism, 2025, 27 (6), pp.3477-3489
ISSN
1462-8902
Publisher
Wiley
Start Page
3477
End Page
3489
Journal / Book Title
Diabetes, Obesity and Metabolism
Volume
27
Issue
6
Copyright Statement
© 2025 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/40176480
Subjects
animal pharmacology
antidiabetic drug
antiobesity drug
ATHEROSCLEROSIS
BROWN ADIPOSE-TISSUE
dyslipidaemia
Endocrinology & Metabolism
FOOD-INTAKE
GENE-EXPRESSION
GLP-1
GLP-1 analogue
GLUCOSE
INTESTINE
Life Sciences & Biomedicine
NERVOUS-SYSTEM
Science & Technology
THERMOGENESIS
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2025-05-02