Abstract
AbstractAntagonism or agonism of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) prevents weight gain and leads to dramatic weight loss in combination with glucagon-like peptide-1 receptor agonists in preclinical models. Based on the genetic evidence supporting GIPR antagonism, we previously developed a mouse anti-murine GIPR antibody (muGIPR-Ab) that protected diet-induced obese (DIO) mice against body weight gain and improved multiple metabolic parameters. This work reconciles the similar preclinical body weight effects of GIPR antagonists and agonists in vivo, and here we show that chronic GIPR agonism desensitizes GIPR activity in primary adipocytes, both differentiated in vitro and adipose tissue in vivo, and functions like a GIPR antagonist. Additionally, GIPR activity in adipocytes is partially responsible for muGIPR-Ab to prevent weight gain in DIO mice, demonstrating a role of adipocyte GIPR in the regulation of adiposity in vivo.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference38 articles.
1. Kelly, A. S. et al. A randomized, controlled trial of liraglutide for adolescents with obesity. New Engl. J. Med. 382, 2117–2128 (2020).
2. Killion, E. A. et al. Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models. Sci. Transl. Med. 10 https://doi.org/10.1126/scitranslmed.aat3392 (2018).
3. Mroz, P. A. et al. Optimized GIP analogs promote body weight lowering in mice through GIPR agonism not antagonism. Mol. Metab. 20, 51–62 (2019).
4. Noerregaard, P. et al. A novel GIP receptor agonist enhances the body weight lowering effect of liraglutide in diet-induced obese mice and has the potential for once-weekly administration in humans. Diabetologia 58, S838 (2015).
5. Norregaard, P. K. et al. A novel GIP analogue, ZP4165, enhances glucagon-like peptide-1-induced body weight loss and improves glycaemic control in rodents. Diabetes Obes. Metab. 20, 60–68 (2018).
Cited by
75 articles.
订阅此论文施引文献
订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献