Sustained Brown Fat Stimulation and Insulin Sensitization by a Humanized Bispecific Antibody Agonist for Fibroblast Growth Factor Receptor 1/βKlotho Complex
| العنوان: | Sustained Brown Fat Stimulation and Insulin Sensitization by a Humanized Bispecific Antibody Agonist for Fibroblast Growth Factor Receptor 1/βKlotho Complex |
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| المؤلفون: | Diana Ronai Dunshee, Jose Zavala-Solorio, Hok Seon Kim, Sharmila Rajan, Yongmei Chen, James A. Ernst, Elizabeth Luis, Ai-Luen Wu, Robert Soriano, Ganesh Kolumam, Amos Baruch, Mark Z. Chen, Raymond K. Tong, Shelby K. Wyatt, Richard A.D. Carano, Christoph Spiess, Owen P. McGuinness, Jean-Michel Vernes, Andrew S. Peterson, Søren Warming, Keith R. Anderson, Xin Y. Rairdan, Junichiro Sonoda, Matthew J. Brauer, Scott Stawicki, Benjamin Haley, Laetitia Comps-Agrar, Jed Ross, Y. Gloria Meng, Johnny Gutierrez, James Ziai, Thomas Gelzleichter, Travis W. Bainbridge, Nicholas Lewin-Koh, Yan Wu, Nicholas van Bruggen, Vineela D. Gandham, Lance Kates, Yingnan Zhang, Dale Stevens |
| المصدر: | EBioMedicine, Vol 2, Iss 7, Pp 730-743 (2015) EBioMedicine |
| بيانات النشر: | Elsevier, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Male, FGF21, medicine.medical_treatment, Bispecific antibody, Adipose tissue, Mice, Obese, lcsh:Medicine, White adipose tissue, Brown adipose tissue, FGF19, Therapeutic antibody, Adipose Tissue, Brown, Antibodies, Bispecific, Insulin, Mice, Inbred BALB C, lcsh:R5-920, NASH, Thermogenesis, Type 2 diabetes, General Medicine, medicine.anatomical_structure, Original Article, Adipose tissue browning, Adiponectin, lcsh:Medicine (General), Protein Binding, medicine.medical_specialty, UCP1, Humanized antibody, Biology, General Biochemistry, Genetics and Molecular Biology, Cell Line, Insulin resistance, Internal medicine, Weight Loss, medicine, Animals, Humans, betaKlotho, Receptor, Fibroblast Growth Factor, Type 1, Obesity, Klotho Proteins, Fibroblast growth factor receptor 1, lcsh:R, Membrane Proteins, Hepatosteatosis, medicine.disease, Fibroblast Growth Factors, Mice, Inbred C57BL, Macaca fascicularis, Endocrinology, HEK293 Cells, FGFR1, Energy Metabolism |
| الوصف: | Dissipating excess calories as heat through therapeutic stimulation of brown adipose tissues (BAT) has been proposed as a potential treatment for obesity-linked disorders. Here, we describe the generation of a humanized effector-less bispecific antibody that activates fibroblast growth factor receptor (FGFR) 1/βKlotho complex, a common receptor for FGF21 and FGF19. Using this molecule, we show that antibody-mediated activation of FGFR1/βKlotho complex in mice induces sustained energy expenditure in BAT, browning of white adipose tissue, weight loss, and improvements in obesity-associated metabolic derangements including insulin resistance, hyperglycemia, dyslipidemia and hepatosteatosis. In mice and cynomolgus monkeys, FGFR1/βKlotho activation increased serum high-molecular-weight adiponectin, which appears to contribute over time by enhancing the amplitude of the metabolic benefits. At the same time, insulin sensitization by FGFR1/βKlotho activation occurs even before the onset of weight loss in a manner that is independent of adiponectin. Together, selective activation of FGFR1/βKlotho complex with a long acting therapeutic antibody represents an attractive approach for the treatment of type 2 diabetes and other obesity-linked disorders through enhanced energy expenditure, insulin sensitization and induction of high-molecular-weight adiponectin. Highlights • A humanized bispecific antibody that selectively activates FGFR1/βKlotho complex was generated. • Anti-FGFR1/βKlotho agonist antibody induced sustained thermogenesis in brown fat and induced weight loss. • Anti-FGFR1/βKlotho agonist antibody improved insulin sensitivity even before the onset of weight loss. |
| اللغة: | English |
| تدمد: | 2352-3964 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::292cc2ae94284197f1952ee9ad725380Test http://www.sciencedirect.com/science/article/pii/S235239641530030XTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....292cc2ae94284197f1952ee9ad725380 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23523964 |
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