Distinct brain regions mediate regulation of food intake in response to GIPR agonism or antagonism.
Distinct brain regions mediate the effects of GIPR agonism and antagonism on appetite and weight loss in mice, but the implications for human treatment remain unclear.
Where it sits
this study against the rest of the cagrilintide (am833) corpusSummary and findings
This study investigates the role of GIPR agonism and antagonism in regulating food intake and weight loss in mice with specific GIPR knockouts. The research focuses on the effects of GIPR modulation in combination with liraglutide and cagrilintide. Results indicate distinct brain regions mediate these effects, but no therapeutic claims are made.
Abstract
The development of dual agonists for the glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) has been a landmark moment in the treatment of type 2 diabetes and obesity. However, for reasons that are incompletely understood, in preclinical and clinical studies, adding either a GIPR agonist or GIPR antagonist to GLP-1R agonism causes additional weight loss<sup>1</sup>. Here we show that distinct brain regions mediate the appetite-suppressing effects of GIPR agonists and the synergistic weight loss effects conferred by GIPR antagonists. We knock out Gipr in either the area postrema (AP) or hypothalamus of mice (Gipr<sup>AP-KO</sup> and Gipr<sup>hypo-KO</sup>, respectively) and compare body weight and food intake responses to GIPR agonists and antagonists, alone and in combination with the GLP-1R agonist liraglutide. Gipr<sup>AP-KO</sup> mice exhibit partial protection against diet-induced obesity, reduced responsiveness to the appetite-suppressing effects of acyl-GIP and a reduced ability of acyl-GIP to prevent avoidance triggered by peptide YY. Weight loss effects of liraglutide are comparable in Gipr<sup>AP-KO</sup> and control mice, and the co-administration of a GIPR antagonist peptide causes similar additional weight loss in both groups. Gipr<sup>hypo-KO</sup> mice, by contrast, exhibit normal appetite suppression by acyl-GIP but enhanced weight loss on liraglutide compared with control mice. Gipr<sup>hypo-KO</sup> also abolishes the synergistic effect of a GIPR antagonist when combined with liraglutide-an effect that is not mediated by nucleus tractus solitarius preproglucagon neurons. GIPR antagonism and Gipr<sup>hypo-KO</sup> also sensitise to cagrilintide-induced weight loss. Overall, our results suggest that the AP is responsible for the appetite-suppressing effects of GIPR agonism but that GIP receptors in the hypothalamus underlie the ability of GIPR antagonism to enhance the weight loss effects of GLP-1R and amylin receptor agonists.
Background
This research addresses the mechanisms by which GIPR agonists and antagonists influence food intake and weight loss. Previous studies have indicated that dual agonists for GLP-1R and GIPR can lead to greater weight loss, but the underlying mechanisms remain unclear. Understanding these mechanisms is crucial for developing effective obesity treatments.
Methods
The study utilized Gipr knockout mice (Gipr<sup>AP-KO</sup> and Gipr<sup>hypo-KO</sup>) to assess responses to GIPR agonists and antagonists, in combination with the GLP-1R agonist liraglutide. Specific doses, duration, and routes of administration are not reported in the abstract. The primary outcome measures included body weight and food intake responses.
Results
Gipr<sup>AP-KO</sup> mice showed partial protection against diet-induced obesity and reduced appetite suppression from acyl-GIP. In contrast, Gipr<sup>hypo-KO</sup> mice experienced enhanced weight loss on liraglutide compared to controls. The study did not provide specific numeric findings for primary endpoints.
Interpretation
The findings suggest that different brain regions are responsible for the effects of GIPR modulation on appetite and weight loss. While the results are statistically significant, the clinical relevance remains uncertain due to the use of animal models. Limitations include potential confounding factors such as small sample sizes and the absence of human data.
Key findings
- Gipr<sup>AP-KO</sup> mice exhibit partial protection against diet-induced obesity, reduced responsiveness to acyl-GIP, and a reduced ability of acyl-GIP to prevent avoidance triggered by peptide YY.
- Weight loss effects of liraglutide are comparable in Gipr<sup>AP-KO</sup> and control mice.
- Gipr<sup>hypo-KO</sup> mice exhibit enhanced weight loss on liraglutide compared with control mice.
- Gipr<sup>hypo-KO</sup> abolishes the synergistic effect of a GIPR antagonist when combined with liraglutide.
- GIPR antagonism and Gipr<sup>hypo-KO</sup> also sensitise to cagrilintide-induced weight loss.
Limitations
- Based on mouse models, which may not translate to humans.
- Specific sample sizes and statistical analyses not reported.
- No long-term follow-up data provided.
- Potential confounding factors not addressed.