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

• Main Authors: Mark Z. Chen (Author), Joshua C. Chang (Author), Jose Zavala-Solorio (Author), Lance Kates (Author), Minh Thai (Author), Annie Ogasawara (Author), Xiaobo Bai (Author), Sean Flanagan (Author), Victor Nunez (Author), Khanhky Phamluong (Author), James Ziai (Author), Robert Newman (Author), Søren Warming (Author), Ganesh Kolumam (Author), Junichiro Sonoda (Author)
• Format: Book
• Published: Elsevier, 2017-11-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 2212-8778; 10.1016/j.molmet.2017.09.003
• Keywords: FGF21; Therapeutic antibody; Agonist antibody; Thermogenesis; Brown adipose tissue; Internal medicine; RC31-1245
• Source: Molecular Metabolism, Vol 6, Iss 11, Pp 1454-1467 (2017)

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 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. Methods: 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. 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/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.