Yashiro Hiroaki, Takagahara Shuichi, Tamura Yumiko Okano, Miyahisa Ikuo, Matsui Junji, Suzuki Hideo, Ikeda Shota, Watanabe Masanori
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa Japan.
PLoS One. 2016 Nov 10;11(11):e0166198. doi: 10.1371/journal.pone.0166198. eCollection 2016.
Obesity is now recognized as a state of chronic low-grade inflammation and is called as metabolic inflammation. Delta-5 desaturase (D5D) is an enzyme that metabolizes dihomo-γ-linolenic acid (DGLA) to arachidonic acid (AA). Thus, D5D inhibition increases DGLA (precursor to anti-inflammatory eicosanoids) while decreasing AA (precursor to pro-inflammatory eicosanoids), and could result in synergistic improvement in the low-grade inflammatory state. Here, we demonstrate reduced insulin resistance and the anti-obesity effect of a D5D selective inhibitor (compound-326), an orally active small-molecule, in a high-fat diet-induced obese (DIO) mouse model. In vivo D5D inhibition was confirmed by determining changes in blood AA/DGLA profiles. In DIO mice, chronic treatment with compound-326 lowered insulin resistance and caused body weight loss without significant impact on cumulative calorie intake. Decreased macrophage infiltration into adipose tissue was expected from mRNA analysis. Increased daily energy expenditure was also observed following administration of compound-326, in line with sustained body weight loss. These data indicate that the novel D5D selective inhibitor, compound-326, will be a new class of drug for the treatment of obese and diabetic patients.
肥胖现在被认为是一种慢性低度炎症状态，被称为代谢性炎症。Δ-5去饱和酶（D5D）是一种将二高-γ-亚麻酸（DGLA）代谢为花生四烯酸（AA）的酶。因此，抑制D5D可增加DGLA（抗炎类二十烷酸的前体），同时减少AA（促炎类二十烷酸的前体），并可能协同改善低度炎症状态。在此，我们在高脂饮食诱导的肥胖（DIO）小鼠模型中证明了一种口服活性小分子D5D选择性抑制剂（化合物-326）具有降低胰岛素抵抗和抗肥胖作用。通过测定血液中AA/DGLA谱的变化来确认体内D5D的抑制情况。在DIO小鼠中，用化合物-326进行慢性治疗可降低胰岛素抵抗并导致体重减轻，而对累积热量摄入无显著影响。mRNA分析表明脂肪组织中的巨噬细胞浸润减少。给予化合物-326后还观察到每日能量消耗增加，这与体重持续减轻一致。这些数据表明，新型D5D选择性抑制剂化合物-326将成为治疗肥胖和糖尿病患者的一类新型药物。
