FGF21 mimetic antibody stimulates UCP1-independent brown fat thermogenesis via FGFR1/βKlotho complex in non-adipocytes
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 βKlotho...
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Published in | Molecular metabolism (Germany) Vol. 6; no. 11; pp. 1454 - 1467 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Germany
Elsevier GmbH
01.11.2017
Elsevier |
Subjects | |
Online Access | Get full text |
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Summary: | 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 βKlotho. Previously, recombinant antibody proteins that activate the FGFR1/βKlotho complex were proposed to act as an FGF21-mimetic; however, in vivo action of these engineered proteins has not been well studied.
We investigated the mechanism by which anti-FGFR1/βKlotho 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.
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.
Collectively, we propose that FGFR1/βKlotho 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.
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•Anti-FGFR1/βKlotho bispecific antibody stimulates energy expenditure in Ucp1-deficient mice.•Anti-FGFR1/βKlotho bispecific antibody stimulates energy expenditure in adipocyte-selective Fgfr1-deficient mice.•Brown adipocyte restricted activation of transgenic FGFR1 does not stimulate energy expenditure.•Anti-FGFR1/βKlotho bispecific antibody mimics FGF21, inducing sweet and alcohol aversion. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2212-8778 2212-8778 |
DOI: | 10.1016/j.molmet.2017.09.003 |