FGF21 mimetic antibody stimulates UCP1-independent brown fat thermogenesis via FGFR1/?Klotho complex in non-adipocytes.

ABSTRACT: 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 ?Klotho. Previously, recombinant antibody proteins that activate the FGFR1/?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/?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/?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.

SUBMITTER: Chen MZ 

PROVIDER: S-EPMC5681280 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature