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首页> 外文期刊>Molecular Metabolism >FGF21 mimetic antibody stimulates UCP1-independent brown fat thermogenesis via FGFR1/@bKlotho complex in non-adipocytes
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FGF21 mimetic antibody stimulates UCP1-independent brown fat thermogenesis via FGFR1/@bKlotho complex in non-adipocytes

机译：FGF21模拟抗体通过非脂肪细胞中的FGFR1 / @ bKlotho复合物刺激UCP1独立的棕色脂肪生热

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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 @bKlotho. Previously, recombinant antibody proteins that activate the FGFR1/@bKlotho 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/@bKlotho 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/@bKlotho 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.
机译：目的：成纤维细胞生长因子21（FGF21）是一种有效的棕色脂肪生热刺激剂，可通过使由成纤维细胞生长因子受体1（FGFR1）和必需的coreceptor @bKlotho组成的受体复合物参与来改善胰岛素敏感性，改善肝脂肪变性并诱导体重减轻。 。以前，有人提出激活FGFR1 / @ bKlotho复合物的重组抗体蛋白起FGF21模拟物的作用。但是，尚未对这些工程蛋白的体内作用进行深入研究。方法：我们使用基因工程小鼠研究了抗FGFR1 / @ bKlotho双特异性抗体（bFKB1）刺激表达UCP1的棕色脂肪细胞生热的机制。抗FGFR1激动剂抗体也用于在转基因小鼠中实现棕色脂肪组织限制的激活。结果：对全球缺乏Ucp1的小鼠和缺乏脂肪的Fgfr1的小鼠的研究表明，bFKB1作用于脂肪细胞远端的靶标，并以独立于UCP1的方式间接刺激棕色脂肪的生热。使用新开发的转基因系统，我们还显示棕色脂肪组织限制了在Ucp1启动子控制下表达的转基因FGFR1的激活不会刺激能量消耗。最后，与其作为FGF21模拟物的作用一致，bFBK1抑制了小鼠中含糖精食物和含酒精水的摄入。结论：总的来说，我们建议FGFR1 / @ bKlotho靶向治疗确实模拟了FGF21的体内作用，并通过脂肪细胞外的受体以及可能在神经系统中刺激了UCP1独立的棕色脂肪生热。

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