Fibroblast activation protein (FAP) as a novel metabolic target.
Fibroblast activation protein (FAP) as a novel metabolic target.
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DOI：
10.1016/j.molmet.2016.07.003
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发表时间：
2016-10
影响因子：
8.1
通讯作者：
Kharitonenkov A
中科院分区：
文献类型：
--
作者：
Sánchez-Garrido MA;Habegger KM;Clemmensen C;Holleman C;Müller TD;Perez-Tilve D;Li P;Agrawal AS;Finan B;Drucker DJ;Tschöp MH;DiMarchi RD;Kharitonenkov A
成纤维细胞活化蛋白（FAP）是属于S9B脯氨酰寡肽酶亚家族的丝氨酸蛋白酶。这种酶与癌症的发展有关，最近有报道称它可以调节FGF21（一种有效的代谢激素）的降解。使用已知的FAP抑制剂塔拉司他（TB），我们探索了FAP抑制对小鼠代谢调节的影响。为了解决这个问题，我们在各种小鼠模型中评估了TB的药理学，包括FGF21、GLP 1和GIP信号传导缺陷的小鼠模型。我们还研究了FAP在体外加工FGF 21的能力和TB阻断FAP酶活性的能力。对饮食诱导的肥胖（DIO）动物施用TB导致体重显著降低、食物消耗和肥胖减少、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TB处理的DIO小鼠中观察到总的和完整的血浆FGF21升高，但在TB的代谢影响显著减弱的瘦动物中未观察到。此外，与未经处理的DIO小鼠形成鲜明对比的是，对肥胖的FGF21敲除动物施用TB对体重或任何其他代谢指标没有明显影响。为了支持这些结果，我们观察到当FAP在体外被TB抑制时，在蛋白质的任一末端都没有人FGF 21的酶降解。我们的结论是，药理学抑制FAP提高了肥胖小鼠的FGF21水平，提供了在瘦动物中未观察到的强大的代谢益处，从而验证了这种酶作为治疗肥胖和糖尿病的新型药物靶点。FAP的药理学抑制降低了肥胖小鼠的体重，改善了葡萄糖和脂质代谢，但对瘦小鼠没有影响。较高剂量的FAP抑制剂Talabostat减少食物摄入，在短期研究中没有任何明显的不良反应。当用塔拉司他治疗时，肥胖的FGF21缺陷小鼠在代谢调节方面没有表现出有意义的变化。塔拉司他的体内作用机制似乎集中在血浆FGF 21的总水平和活性水平的增加上。FAP抑制单独或与DPP4组合被提出作为治疗代谢疾病的新方法。
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. Pharmacological inhibition of FAP reduces weight, improves glucose and lipid metabolism in obese, but not lean mice. FAP inhibitor Talabostat at higher doses lessens food intake, without any apparent adverse effects in short term studies. Obese FGF21 deficient mice did not exhibit meaningful change in metabolic regulation when treated with Talabostat. The mechanism of Talabostat in vivo action appears to center on an increase in total and active levels of plasma FGF21. FAP inhibition alone, or in combination with DPP4 is proposed as a novel approach to treat metabolic diseases.
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DOI：
10.1016/j.bbrc.2007.06.068
发表时间：
2007-08-24
影响因子：
3.1
作者：
Lundasen, Thomas;Hunt, Mary C.;Rudling, Mats
通讯作者：
Rudling, Mats
影响因子：
6.1
作者：
Cunningham, Charles Casey
通讯作者：
Cunningham, Charles Casey
影响因子：
3.7
作者：
Hecht R;Li YS;Sun J;Belouski E;Hall M;Hager T;Yie J;Wang W;Winters D;Smith S;Spahr C;Tam LT;Shen Z;Stanislaus S;Chinookoswong N;Lau Y;Sickmier A;Michaels ML;Boone T;Véniant MM;Xu J
通讯作者：
Xu J
影响因子：
4.8
作者：
Assini, Julia M.;Mulvihill, Erin E.;Huff, Murray W.
通讯作者：
Huff, Murray W.
影响因子：
29
作者：
Badman, Michael K.;Pissios, Pavlos;Maratos-Flier, Eleftheria
通讯作者：
Maratos-Flier, Eleftheria