Oppositely biased glucagon-like peptide-1 receptor agonism does not differentially affect lipid metabolism in APOE*3-Leiden CETP mice.

AIMS: [D,G,K.C16 diacid]exendin-4 (acyl-ExD3) and [F,G,K.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[H]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 [H]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.