Journal article
FGF19, FGF21, and an FGFR1/β-Klotho-Activating Antibody Act on the Nervous System to Regulate Body Weight and Glycemia
Cell metabolism, Vol.26(5), pp.709-718.e3
11/07/2017
DOI: 10.1016/j.cmet.2017.09.005
PMCID: PMC5679468
PMID: 28988823
Abstract
Despite the different physiologic functions of FGF19 and FGF21 as hormonal regulators of fed and fasted metabolism, their pharmacologic administration causes similar increases in energy expenditure, weight loss, and enhanced insulin sensitivity in obese animals. Here, in genetic loss-of-function studies of the shared co-receptor β-Klotho, we show that these pharmacologic effects are mediated through a common, tissue-specific pathway. Surprisingly, FGF19 and FGF21 actions in liver and adipose tissue are not required for their longer-term weight loss and glycemic effects. In contrast, β-Klotho in neurons is essential for both FGF19 and FGF21 to cause weight loss and lower glucose and insulin levels. We further show an FGF21 mimetic antibody that activates the FGF receptor 1/β-Klotho complex also requires neuronal β-Klotho for its metabolic effects. These studies highlight the importance of the nervous system in mediating the beneficial weight loss and glycemic effects of endocrine FGF drugs.
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•FGF19 and FGF21 act through a common tissue-specific mechanism to cause weight loss•The nervous system is the direct target for FGF19 and FGF21 effects on weight loss•β-Klotho in adipose and liver is dispensable for FGF19/FGF21 effects on weight loss•An FGF21 mimetic antibody mediates its weight loss effects via the nervous system
The tissue-specific actions of FGF19- and FGF21-based therapeutics have stimulated considerable scientific and clinical interest. Lan et al. show that FGF19, FGF21, and an antibody mimetic require the co-receptor, β-Klotho, in neurons, but not hepatocytes or adipocytes, to mediate their beneficial metabolic effects on body weight and glycemia.
Details
- Title: Subtitle
- FGF19, FGF21, and an FGFR1/β-Klotho-Activating Antibody Act on the Nervous System to Regulate Body Weight and Glycemia
- Creators
- Tian Lan - Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USADonald A Morgan - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USAKamal Rahmouni - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USAJunichiro Sonoda - Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USAXiaorong Fu - Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX 75390, USAShawn C Burgess - Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USAWilliam L Holland - Touchstone Diabetes Center, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USASteven A Kliewer - Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USADavid J Mangelsdorf - Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA
- Resource Type
- Journal article
- Publication Details
- Cell metabolism, Vol.26(5), pp.709-718.e3
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.cmet.2017.09.005
- PMID
- 28988823
- PMCID
- PMC5679468
- ISSN
- 1550-4131
- eISSN
- 1932-7420
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: 1P01AG051459, R01DK067158; DOI: 10.13039/100000011, name: Howard Hughes Medical Institute; DOI: 10.13039/100000928, name: Welch Foundation, award: I-1275, I-1558, I-1804
- Language
- English
- Date published
- 11/07/2017
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984040257502771
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