Sánchez-Garrido Miguel Angel, Habegger Kirk M, Clemmensen Christoffer, Holleman Cassie, Müller Timo D, Perez-Tilve Diego, Li Pengyun, Agrawal Archita S, Finan Brian, Drucker Daniel J, Tschöp Matthias H, DiMarchi Richard D, Kharitonenkov Alexei
Institute for Diabetes and Obesity (IDO), Helmholtz Diabetes Center, Munich, 85748, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, 85748, Germany; German Center for Diabetes Research (DZD), Neuherberg, 85764, Germany.
Department of Medicine Endocrinology, Diabetes & Metabolism, University of Alabama at Birmingham, Birmingham, AL, 35294, United States.
Mol Metab. 2016 Jul 16;5(10):1015-1024. doi: 10.1016/j.molmet.2016.07.003. eCollection 2016 Oct.
Fibroblast activation protein (FAP) is a serine protease belonging to a S9B prolyl oligopeptidase subfamily. This enzyme has been implicated in cancer development and recently reported to regulate degradation of FGF21, a potent metabolic hormone. Using a known FAP inhibitor, talabostat (TB), we explored the impact of FAP inhibition on metabolic regulation in mice.
To address this question we evaluated the pharmacology of TB in various mouse models including those deficient in FGF21, GLP1 and GIP signaling. We also studied the ability of FAP to process FGF21 in vitro and TB to block FAP enzymatic activity.
TB administration to diet-induced obese (DIO) animals led to profound decreases in body weight, reduced food consumption and adiposity, increased energy expenditure, improved glucose tolerance and insulin sensitivity, and lowered cholesterol levels. Total and intact plasma FGF21 were observed to be elevated in TB-treated DIO mice but not lean animals where the metabolic impact of TB was significantly attenuated. Furthermore, and in stark contrast to naïve DIO mice, the administration of TB to obese FGF21 knockout animals demonstrated no appreciable effect on body weight or any other measures of metabolism. In support of these results we observed no enzymatic degradation of human FGF21 at either end of the protein when FAP was inhibited in vitro by TB.
We conclude that pharmacological inhibition of FAP enhances levels of FGF21 in obese mice to provide robust metabolic benefits not observed in lean animals, thus validating this enzyme as a novel drug target for the treatment of obesity and diabetes.
成纤维细胞活化蛋白（FAP）是一种属于S9B脯氨酰寡肽酶亚家族的丝氨酸蛋白酶。该酶与癌症发展有关，最近有报道称其可调节强效代谢激素FGF21的降解。我们使用已知的FAP抑制剂他拉泊司他（TB），探讨了FAP抑制对小鼠代谢调节的影响。
为解决这个问题，我们在各种小鼠模型中评估了TB的药理学特性，包括那些缺乏FGF21、GLP1和GIP信号传导的模型。我们还研究了FAP在体外加工FGF21的能力以及TB阻断FAP酶活性的能力。
给饮食诱导肥胖（DIO）动物施用TB导致体重显著下降、食物摄入量和肥胖程度降低、能量消耗增加、葡萄糖耐量和胰岛素敏感性改善以及胆固醇水平降低。在接受TB治疗的DIO小鼠中，观察到血浆总FGF21和完整FGF21升高，但在瘦小鼠中未观察到这种情况，TB对瘦小鼠的代谢影响明显减弱。此外，与未处理的DIO小鼠形成鲜明对比的是，给肥胖FGF21基因敲除动物施用TB对体重或任何其他代谢指标均无明显影响。支持这些结果的是，当在体外使用TB抑制FAP时，我们未观察到人类FGF21蛋白两端有酶促降解。
我们得出结论，FAP的药理学抑制可提高肥胖小鼠体内FGF21的水平，从而带来瘦小鼠未观察到的强大代谢益处，因此验证了该酶作为治疗肥胖和糖尿病的新型药物靶点的有效性。
