Activity of dietary fatty acids on FFA1 and FFA4 and characterisation of pinolenic acid as a dual FFA1/FFA4 agonist with potential effect against metabolic diseases
Activity of dietary fatty acids on FFA1 and FFA4 and characterisation of pinolenic acid as a dual FFA1/FFA4 agonist with potential effect against metabolic diseases
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DOI：
10.1017/s000711451500118x
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发表时间：
2015-06-14
影响因子：
3.6
通讯作者：
Ulven, Trond
中科院分区：
文献类型：
--
作者：
Christiansen, Elisabeth;Watterson, Kenneth R.;Ulven, Trond
各种食物都与抗胰岛素抵抗和2型糖尿病等代谢疾病的作用有关;然而，它们的作用机制大多不清楚。脂肪酸可能通过作为信号分子的前体或通过对受体的直接活性而起作用。中链和长链NEFA受体FFA 1（游离脂肪酸受体1，以前称为GPR 40）与葡萄糖刺激的胰岛素分泌的增强有关，而FFA 4（游离脂肪酸受体4，以前称为GPR 120）与胰岛素增敏和抗炎作用有关，据报道，这两种受体都能保护胰岛并促进食欲和葡萄糖调节激素的分泌。假设FFA 1和FFA 4介导饮食成分的治疗作用，我们筛选了广泛选择的NEFA对FFA 1和FFA 4，并在浓度-响应曲线中表征活性化合物。在筛选的化合物中，松油酸（松仁油的一种成分）被鉴定为相对强效和有效的双重FFA 1/FFA 4激动剂，并且通过额外的体外表征证实了其用于进一步研究的适用性。在小鼠的急性葡萄糖耐量试验中测试了松仁油和游离的和酯化的纯皮诺敛酸。与玉米油相比，松仁油显示出适度但显著的葡萄糖耐量改善。纯皮诺敛酸或其乙酯对葡萄糖耐量有显著的改善作用。总之，本结果表明皮诺敛酸是一种相对强效和有效的双重FFA 1/FFA 4激动剂，在急性小鼠模型中发挥抗糖尿病作用。因此，该化合物作为预防或对抗代谢疾病的潜在活性膳食成分值得关注。
Various foods are associated with effects against metabolic diseases such as insulin resistance and type 2 diabetes; however, their mechanisms of action are mostly unclear. Fatty acids may contribute by acting as precursors of signalling molecules or by direct activity on receptors. The medium- and long-chain NEFA receptor FFA1 (free fatty acid receptor 1, previously known as GPR40) has been linked to enhancement of glucose-stimulated insulin secretion, whereas FFA4 (free fatty acid receptor 4, previously known as GPR120) has been associated with insulin-sensitising and anti-inflammatory effects, and both receptors are reported to protect pancreatic islets and promote secretion of appetite and glucose-regulating hormones. Hypothesising that FFA1 and FFA4 mediate therapeutic effects of dietary components, we screened a broad selection of NEFA on FFA1 and FFA4 and characterised active compounds in concentration-response curves. Of the screened compounds, pinolenic acid, a constituent of pine nut oil, was identified as a relatively potent and efficacious dual FFA1/FFA4 agonist, and its suitability for further studies was confirmed by additional in vitro characterisation. Pine nut oil and free and esterified pure pinolenic acid were tested in an acute glucose tolerance test in mice. Pine nut oil showed a moderately but significantly improved glucose tolerance compared with maize oil. Pure pinolenic acid or ethyl ester gave robust and highly significant improvements of glucose tolerance. In conclusion, the present results indicate that pinolenic acid is a comparatively potent and efficacious dual FFA1/FFA4 agonist that exerts antidiabetic effects in an acute mouse model. The compound thus deserves attention as a potential active dietary ingredient to prevent or counteract metabolic diseases.