Characterization of a FGF19 variant with altered receptor specificity revealed a central role for FGFR1c in the regulation of glucose metabolism.
Characterization of a FGF19 variant with altered receptor specificity revealed a central role for FGFR1c in the regulation of glucose metabolism.
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DOI：
10.1371/journal.pone.0033603
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Ge H;Baribault H;Vonderfecht S;Lemon B;Weiszmann J;Gardner J;Lee KJ;Gupte J;Mookherjee P;Wang M;Sheng J;Wu X;Li Y
糖尿病和相关的代谢疾病在世界范围内已达到流行病的比例，并且对于既有效又安全的新疗法存在明显未满足的医疗需求。FGF 19和FGF 21是FGF家族的独特成员，其作为内分泌激素起作用。两者都对正常化葡萄糖、脂质和能量稳态具有有效作用，因此，代表了对抗2型糖尿病和肥胖症日益增长的流行病的有吸引力的潜在下一代疗法。负责这些令人印象深刻的代谢作用的机制仍然未知。虽然FGF 19和FGF 21在体外存在共受体βKlotho的情况下都可以激活FGFR 1c、2c和3c，但哪种受体负责体内观察到的代谢活性仍然未知。在这里，我们已经产生了FGF 19的变体，FGF 19 -7，它改变了受体特异性，对FGFR 1c有很强的偏好。我们发现，FGF 19 -7在调节饮食诱导的肥胖和瘦素缺乏小鼠模型中的葡萄糖、脂质和能量代谢方面与野生型FGF 19同样有效。这些结果首次直接证明了βKlotho/FGFR 1c受体复合物在葡萄糖和脂质调节中的核心作用，并且还强烈表明单独激活该受体复合物可能足以实现内分泌FGF分子的所有代谢功能。
Diabetes and associated metabolic conditions have reached pandemic proportions worldwide, and there is a clear unmet medical need for new therapies that are both effective and safe. FGF19 and FGF21 are distinctive members of the FGF family that function as endocrine hormones. Both have potent effects on normalizing glucose, lipid, and energy homeostasis, and therefore, represent attractive potential next generation therapies for combating the growing epidemics of type 2 diabetes and obesity. The mechanism responsible for these impressive metabolic effects remains unknown. While both FGF19 and FGF21 can activate FGFRs 1c, 2c, and 3c in the presence of co-receptor βKlotho in vitro, which receptor is responsible for the metabolic activities observed in vivo remains unknown. Here we have generated a variant of FGF19, FGF19-7, that has altered receptor specificity with a strong bias toward FGFR1c. We show that FGF19-7 is equally efficacious as wild type FGF19 in regulating glucose, lipid, and energy metabolism in both diet-induced obesity and leptin-deficient mouse models. These results are the first direct demonstration of the central role of the βKlotho/FGFR1c receptor complex in glucose and lipid regulation, and also strongly suggest that activation of this receptor complex alone might be sufficient to achieve all the metabolic functions of endocrine FGF molecules.
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DOI：
10.1073/pnas.0701600104
发表时间：
2007-05-01
影响因子：
11.1
作者：
Ogawa, Yasushi;Kurosu, Hiroshi;Kuro-o, Makoto
通讯作者：
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DOI：
10.1016/j.bbagen.2008.09.001
发表时间：
2009-01-01
影响因子：
3
作者：
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6
作者：
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French, DM
影响因子：
4.8
作者：
Wu, Xinle;Lemon, Bryan;Li, Yang
通讯作者：
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影响因子：
5.3
作者：
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