Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models
| العنوان: | Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models |
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| المؤلفون: | Brandon C. P. Clavette, Xiaoshan Min, Joanne Lin, Elizabeth A. Killion, Robert J.M. Kurzeja, David Lloyd, Liying Deng, Zhulun Wang, Clarence Hale, Christopher Murawsky, Stone D.-H. Shi, Murielle M. Véniant, Jinghong Wang, James B. Rottman, Christina Abbott, Todd Hager, Lu Shu Chen, Junming Yie, Ian Foltz, Qing Chen, Stephen A. Thibault, Darren L. Bates, Renee Komorowski, Larissa Atangan, Glenn Sivits, Tina Meng |
| المصدر: | Science Translational Medicine. 10 |
| بيانات النشر: | American Association for the Advancement of Science (AAAS), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Primates, 0301 basic medicine, endocrine system, medicine.medical_specialty, Recombinant Fusion Proteins, Glucagon-Like Peptides, Mice, Obese, Genome-wide association study, Gastric Inhibitory Polypeptide, Weight Gain, Antibodies, Glucagon-Like Peptide-1 Receptor, Receptors, Gastrointestinal Hormone, 03 medical and health sciences, 0302 clinical medicine, Weight loss, Insulin-Secreting Cells, Internal medicine, Weight Loss, Conditional gene knockout, Adipocytes, Animals, Humans, Medicine, Obesity, Receptor, Respiratory exchange ratio, biology, business.industry, Respiration, Feeding Behavior, General Medicine, Liraglutide, medicine.disease, Diet, Immunoglobulin Fc Fragments, 030104 developmental biology, Endocrinology, 030220 oncology & carcinogenesis, Knockout mouse, biology.protein, Drug Therapy, Combination, medicine.symptom, Antibody, business, hormones, hormone substitutes, and hormone antagonists |
| الوصف: | Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) has been identified in multiple genome-wide association studies (GWAS) as a contributor to obesity, and GIPR knockout mice are protected against diet-induced obesity (DIO). On the basis of this genetic evidence, we developed anti-GIPR antagonistic antibodies as a potential therapeutic strategy for the treatment of obesity and observed that a mouse anti-murine GIPR antibody (muGIPR-Ab) protected against body weight gain, improved multiple metabolic parameters, and was associated with reduced food intake and resting respiratory exchange ratio (RER) in DIO mice. We replicated these results in obese nonhuman primates (NHPs) using an anti-human GIPR antibody (hGIPR-Ab) and found that weight loss was more pronounced than in mice. In addition, we observed enhanced weight loss in DIO mice and NHPs when anti-GIPR antibodies were codosed with glucagon-like peptide-1 receptor (GLP-1R) agonists. Mechanistic and crystallographic studies demonstrated that hGIPR-Ab displaced GIP and bound to GIPR using the same conserved hydrophobic residues as GIP. Further, using a conditional knockout mouse model, we excluded the role of GIPR in pancreatic β-cells in the regulation of body weight and response to GIPR antagonism. In conclusion, these data provide preclinical validation of a therapeutic approach to treat obesity with anti-GIPR antibodies. |
| تدمد: | 1946-6242 1946-6234 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4219a5cd6927493203264b2541e2f88bTest https://doi.org/10.1126/scitranslmed.aat3392Test |
| رقم الانضمام: | edsair.doi.dedup.....4219a5cd6927493203264b2541e2f88b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19466242 19466234 |
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