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

• Published in: Molecular metabolism (Germany) Vol. 6; no. 11; pp. 1454 - 1467
• Main Authors: Chen, Mark Z., Chang, Joshua C., Zavala-Solorio, Jose, Kates, Lance, Thai, Minh, Ogasawara, Annie, Bai, Xiaobo, Flanagan, Sean, Nunez, Victor, Phamluong, Khanhky, Ziai, James, Newman, Robert, Warming, Søren, Kolumam, Ganesh, Sonoda, Junichiro
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.11.2017; Elsevier
• Subjects: Adipocytes, Brown - metabolism; Adipose Tissue, Brown - metabolism; Adipose Tissue, White - metabolism; Agonist antibody; Animals; Antibodies - metabolism; Brown adipose tissue; Energy Metabolism - physiology; FGF21; Fibroblast Growth Factors - metabolism; Membrane Proteins - agonists; Membrane Proteins - immunology; Membrane Proteins - metabolism; Mice; Mice, Knockout; Mice, Transgenic; Mitochondrial Proteins - metabolism; Obesity - metabolism; Original; Receptor, Fibroblast Growth Factor, Type 1 - agonists; Receptor, Fibroblast Growth Factor, Type 1 - immunology; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; Therapeutic antibody; Thermogenesis; Thermogenesis - genetics; Thermogenesis - physiology; Uncoupling Protein 1 - genetics; Uncoupling Protein 1 - metabolism; Weight Loss; EE; KLB; Agonist antibody; ingWAT; Therapeutic antibody; ECD; HFD; FDG; UCP1; Brown adipose tissue; eWAT; WAT; MAPK; NASH; AUC; Thermogenesis; HMW; BAT; iBAT; FGF21; FGFR1
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2017.09.003

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. [Display omitted] •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.