Body weight lowering effect of glucose-dependent insulinotropic polypeptide and glucagon-like peptide receptor agonists is more efficient in RAMP1/3 KO than in WT mice

Jul 16, 2023European journal of pharmacology

Weight loss from glucose-dependent insulin and glucagon-like peptide treatments is stronger in mice lacking RAMP1 and RAMP3 compared to normal mice

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Abstract

Combined treatment with GLP-1R and GIPR agonists reduced body weight synergistically, particularly in RAMP1/3 knockout mice.

Mono-agonists of GLP-1R and GIPR had minimal effects on body weight in both wild-type and RAMP1/3 knockout mice.
The combination of GLP-1R and GIPR agonists significantly decreased body weight, with a more pronounced effect in RAMP1/3 knockout mice.
GLP-1R and GIP/GLP-1R agonist treatments improved glucose tolerance in both mouse types.
In the absence of RAMPs, there was an improvement in the HOMA-IR score, indicating enhanced insulin sensitivity.

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The glucose-dependent insulinotropic polypeptide (GIPR) and glucagon-like peptide (GLP-1R) receptor agonists are insulin secretagogues that have long been shown to improve glycemic control and dual agonists have demonstrated successful weight loss in the clinic. GIPR and GLP-1R populations are located in the dorsal vagal complex where receptor activity-modifying proteins (RAMPs) are also present. According to recent literature, RAMPs not only regulate the signaling of the calcitonin receptor, but also that of other class B G-protein coupled receptors, including members of the glucagon receptor family such as GLP-1R and GIPR. The aim of this study was to investigate whether the absence of RAMP1 and RAMP3 interferes with the action of GIPR and GLP-1R agonists on body weight maintenance and glucose control. To this end, WT and RAMP 1/3 KO mice were fed a 45% high fat diet for 22 weeks and were injected daily with GLP-1R agonist (2 nmol/kg/d; NN0113-2220), GIPR agonist (30 nmol/kg/d; NN0441-0329) or both for 3 weeks. While the mono-agonists exerted little to no body weight lowering and anorectic effects in WT or RAMP1/3 KO mice, but at the given doses, when both compounds were administered together, they synergistically reduced body weight, with a greater effect observed in KO mice. Finally, GLP-1R and GIP/GLP-1R agonist treatment led to improved glucose tolerance, but the absence of RAMPs resulted in an improvement of the HOMA-IR score. These data suggest that RAMPs may play a crucial role in modulating the pharmacological actions of GLP-1 and GIP receptors.

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Body weight lowering effect of glucose-dependent insulinotropic polypeptide and glucagon-like peptide receptor agonists is more efficient in RAMP1/3 KO than in WT mice

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