Antibody-mediated activation of the FGFR1/Klothoβ complex corrects metabolic dysfunction and alters food preference in obese humans
| العنوان: | Antibody-mediated activation of the FGFR1/Klothoβ complex corrects metabolic dysfunction and alters food preference in obese humans |
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| المؤلفون: | Chin Wong, Thomas Gelzleichter, Junichiro Sonoda, Amos Baruch, Linda Morrow, Suresh Dheerendra, Leslie W. Chinn, Richard Boismenu, Eric Wakshull, Maria E. Wilson, Puneet S. Arora, Shan Chen, Anjali Vaze, Johnny Gutierrez, Nicholas Lewin-Koh |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, obesity, Medical Sciences, FGF21, Adipose tissue, Mice, 0302 clinical medicine, Weight loss, Homeostasis, Medicine, Multidisciplinary, biology, Middle Aged, Biological Sciences, Adipose Tissue, Female, Adiponectin, Antibody, medicine.symptom, FGF21 receptor activation, Adult, Agonist, medicine.medical_specialty, Adolescent, medicine.drug_class, 030209 endocrinology & metabolism, Antibodies, Food Preferences, Young Adult, 03 medical and health sciences, Internal medicine, Weight Loss, Animals, Humans, Receptor, Fibroblast Growth Factor, Type 1, Aged, business.industry, Fibroblast growth factor receptor 1, Body Weight, medicine.disease, Obesity, Fibroblast Growth Factors, stomatognathic diseases, Macaca fascicularis, 030104 developmental biology, Endocrinology, biology.protein, food preference, business, metabolism, Biomarkers |
| الوصف: | Significance Fibroblast growth factor 21 (FGF21) controls metabolic organ homeostasis and eating behavior via FGF receptor 1/Klothoβ (FGFR1/KLB) complexes. Here we show that a bispecific anti-FGFR1/KLB agonist antibody, BFKB8488A, mimics the actions of FGF21 in monkeys and humans. BFKB8488A induced marked weight loss in obese monkeys while elevating expression of FGFR1 target genes in adipose tissue. A clinical study in overweight human participants demonstrated that a single dose of BFKB8488A caused transient body weight reduction, sustained improvement in cardiometabolic parameters, and a trend toward reduction in preference for sweet taste and carbohydrate intake. These data suggest that antibody-mediated activation of the FGFR1/KLB complex in humans recapitulates the effects of FGF21 and can be used as therapy for obesity-related metabolic defects. Fibroblast growth factor 21 (FGF21) controls metabolic organ homeostasis and eating/drinking behavior via FGF receptor 1/Klothoβ (FGFR1/KLB) complexes expressed in adipocytes, pancreatic acinar cells, and the nervous system in mice. Chronic administration of recombinant FGF21 or engineered variants improves metabolic health in rodents, nonhuman primates, and humans; however, the rapid turnover of these molecules limits therapeutic utility. Here we show that the bispecific anti-FGFR1/KLB agonist antibody BFKB8488A induced marked weight loss in obese cynomolgus monkeys while elevating serum adiponectin and the adipose expression of FGFR1 target genes, demonstrating its action as an FGF21 mimetic. In a randomized, placebo-controlled, single ascending-dose study in overweight/obese human participants, subcutaneous BFKB8488A injection caused transient body weight reduction, sustained improvement in cardiometabolic parameters, and a trend toward reduction in preference for sweet taste and carbohydrate intake. These data suggest that specific activation of the FGFR1/KLB complex in humans can be used as therapy for obesity-related metabolic defects. |
| تدمد: | 1091-6490 0027-8424 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ecb1e6fc5999a3fd66bc3ad16e368b18Test https://doi.org/10.1073/pnas.2012073117Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ecb1e6fc5999a3fd66bc3ad16e368b18 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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