FGF21 mimetic antibody stimulates UCP1-independent brown fat thermogenesis via FGFR1/βKlotho complex in non-adipocytes.
FGF21 mimetic antibody stimulates UCP1-independent brown fat thermogenesis via FGFR1/βKlotho complex in non-adipocytes.
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DOI：
10.1016/j.molmet.2017.09.003
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发表时间：
2017-11
影响因子：
8.1
通讯作者：
Sonoda J
中科院分区：
文献类型：
--
作者：
Chen MZ;Chang JC;Zavala-Solorio J;Kates L;Thai M;Ogasawara A;Bai X;Flanagan S;Nunez V;Phamluong K;Ziai J;Newman R;Warming S;Kolumam G;Sonoda J
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，通过结合由成纤维细胞生长因子受体1(FGFR1)和必需的辅受体βKlotho组成的受体复合体，提高胰岛素敏感性，改善肝骨病，并诱导体重减轻。以前，激活FGFR1/βKlotho复合体的重组抗体蛋白被认为是FGF21的模拟物；然而，这些工程蛋白在体内的作用尚未得到很好的研究。我们利用基因工程小鼠研究了抗FGFR1/βKlotho双特异性抗体(BFKB1)刺激表达UCP1的棕色脂肪细胞产热的机制。抗FGFR1激动剂抗体也被用来在转基因小鼠中实现棕色脂肪组织限制性激活。对全局Ucp1缺陷小鼠和脂肪特异性FGFR1缺陷小鼠的研究表明，bFKB1作用于脂肪细胞远端的靶点，并以UCP1不依赖的方式间接刺激棕色脂肪的产热。利用新开发的转基因系统，我们还表明，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，但不刺激能量消耗。最后，与其作为FGF21模拟物的作用一致，bFBK1抑制小鼠对含糖精的食物和含酒精的水的摄入。总之，我们认为FGFR1/βKlotho靶向治疗确实模仿了FGF21在体内的作用，并通过脂肪细胞外的受体刺激UCP1非依赖的棕色脂肪产热，可能是在神经系统。抗FGFR1Klotho双特异性抗体可刺激β缺陷小鼠的能量消耗。抗FGFR1/βKlotho双特异性抗体刺激脂肪细胞选择性FGFR1缺陷小鼠的能量消耗。棕色脂肪细胞限制激活转基因FGFR1不刺激能量消耗。抗FGFR1Klotho双特异性抗体模拟FGF21，引起甜味和酒精厌恶。
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. 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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影响因子：
1.8
作者：
Cirera S
通讯作者：
Cirera S
DOI：
10.1097/med.0b013e328337a81f
发表时间：
2010-04
期刊：
Current opinion in endocrinology, diabetes, and obesity
影响因子：
--
作者：
Cypess AM;Kahn CR
通讯作者：
Kahn CR
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
4.6
作者：
Hoch, RV;Soriano, P
通讯作者：
Soriano, P
影响因子：
4.8
作者：
Golozoubova, V;Hohtola, E;Nedergaard, J
通讯作者：
Nedergaard, J