期刊
MOLECULAR METABOLISM
卷 6, 期 11, 页码 1454-1467出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.molmet.2017.09.003
关键词
FGF21; Therapeutic antibody; Agonist antibody; Thermogenesis; Brown adipose tissue
Objective: Fibroblast Growth Factor 21 (FGF21) is a potent stimulator of brown fat thermogenesis that improves insulin sensitivity, ameliorates hepatosteatosis, and induces weight loss by engaging the receptor complex comprised of Fibroblast Growth Factor Receptor 1 (FGFR1) and the requisite coreceptor beta Klotho. Previously, recombinant antibody proteins that activate the FGFR1/beta Klotho complex were proposed to act as an FGF21-mimetic; however, in vivo action of these engineered proteins has not been well studied. Methods: We investigated the mechanism by which anti-FGFR1/beta Klotho bispecific antibody (bFKB1) stimulates thermogenesis in UCP1-expressing brown adipocytes using genetically engineered mice. Anti-FGFR1 agonist antibody was also used to achieve brown adipose tissue restricted activation in transgenic mice. Results: Studies with global Ucp1-deficient mice and adipose-specific Fgfr1 deficient mice demonstrated that bFKB1 acts on targets distal to adipocytes and indirectly stimulates brown adipose thermogenesis in a UCP1-independent manner. Using a newly developed transgenic system, we also show that brown adipose tissue restricted activation of a transgenic FGFR1 expressed under the control of Ucp1 promoter does not stimulate energy expenditure. Finally, consistent with its action as a FGF21 mimetic, bFBK1 suppresses intake of saccharin-containing food and alcohol containing water in mice. Conclusions: Collectively, we propose that FGFR1/beta Klotho targeted therapy indeed mimics the action of FGF21 in vivo and stimulates UCP1-independent brown fat thermogenesis through receptors outside of adipocytes and likely in the nervous system. (C) 2017 Genentech, Inc. Published by Elsevier GmbH.
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