Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.
MabCent-SFI, UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
Eur J Med Chem. 2018 Jul 15;155:736-753. doi: 10.1016/j.ejmech.2018.06.034. Epub 2018 Jun 18.
Obesity and associated disorders such as metabolic syndrome and type 2 diabetes (T2D) have reached epidemic proportions. Several natural products have been reported as Peroxisome Proliferator-Activated Receptor (PPAR) agonists, functioning as lead compounds towards developing new anti-diabetic drugs due to adverse side effects of existing PPAR drugs. We recently isolated and identified (7E)-9-oxohexadec-7-enoic acid (1) and (10E)-9-oxohexadec-10-enoic acid (2) from the marine algae Chaetoceros karianus. Herein we report the total synthesis, pharmacological characterization, and biological evaluations of these naturally occurring oxo-fatty acids (oFAs). The syntheses of 1 and 2 afforded sufficient material for extensive biological evaluations. Both oFAs show an appreciable dose-dependent activation of PPARα and -γ, with EC values in the micromolar range, and an ability to regulate important PPAR target genes in hepatocytes and adipocytes. Moreover, both 1 and 2 are able to drive adipogenesis when evaluated in the Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocyte cell model, but with lowered expression of adipocyte markers and reduced lipid accumulation compared to the drug rosiglitazone. This seems to be caused by a transient upregulation of PPARγ and C/EBPα expression. Importantly, whole transcriptome analysis shows that both compounds induce anti-diabetic gene programs in adipocytes by upregulating insulin-sensitizing adipokines and repressing pro-inflammatory cytokines.
肥胖症及相关疾病，如代谢综合征和 2 型糖尿病（T2D），已达到流行程度。已有几种天然产物被报道为过氧化物酶体增殖物激活受体（PPAR）激动剂，由于现有 PPAR 药物的不良反应，它们可作为开发新型抗糖尿病药物的先导化合物。我们最近从海洋藻类 Chaetoceros karianus 中分离并鉴定了（7E）-9-氧代十六碳-7-烯酸（1）和（10E）-9-氧代十六碳-10-烯酸（2）。在此，我们报告了这些天然存在的过氧脂肪酸（oFAs）的全合成、药理学特征和生物学评价。1 和 2 的合成提供了足够的材料进行广泛的生物学评价。这两种 oFAs 均表现出可观的剂量依赖性的 PPARα 和 -γ 激活作用，EC 值在微摩尔范围内，并能够调节肝细胞和脂肪细胞中重要的 PPAR 靶基因。此外，在 Simpson-Golabi-Behmel 综合征（SGBS）前脂肪细胞模型中进行评估时，1 和 2 均能够驱动脂肪生成，但与药物罗格列酮相比，脂肪细胞标志物的表达降低且脂质积累减少。这似乎是由于 PPARγ 和 C/EBPα 表达的短暂上调所致。重要的是，全转录组分析表明，这两种化合物通过上调胰岛素敏感的脂肪因子和抑制促炎细胞因子，在脂肪细胞中诱导抗糖尿病基因程序。
