Kim Minjee, Song Kwangho, Kim Yeong Shik
Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Int Immunopharmacol. 2017 Aug;49:187-194. doi: 10.1016/j.intimp.2017.05.037. Epub 2017 Jun 7.
Obesity is characterized by a massive infiltration of the adipose tissue by macrophages. Adipocytes, together with macrophages create a crosstalk between inflammation and insulin resistance. Excess saturated FFA, such as palmitate, absorbed via the portal system may cause glucose intolerance and inflammation, which leads to insulin resistance. In this study, we aimed to evaluate the potency of alantolactone (AL), a sesquiterpene lactone isolated from Inula helenium in reducing palmitate-induced glucose intolerance, fat accumulation, and inflammation in 3T3-L1 adipocytes and adipocyte-macrophage co-culture system (3T3-L1-RAW264.7). We observed that palmitate reduced glucose uptake and increased fat accumulation, which indicated dysfunctional adipocytes with inadequate lipid storage. However, AL treatment reversed these changes in a dose-dependent manner (P<0.05). Palmitate activated c-Jun N-terminal kinases (JNK) and IκB kinase β/α (IKKβ/α) phosphorylation, and increased the levels of the proinflammatory cytokines (tumor necrosis factor-α and interleukin-6 [IL-6]) and chemokines (monocyte chemoattractant protein-1 [MCP-1]). AL treatment selectively reduced JNK-associated mitogen-activated protein kinase pathway (JNK and extracellular signal-regulated kinase phosphorylation). However, it did not affect NF-κB pathway in adipocytes. In addition, AL decreased the gene expression of JNK upregulating factor, toll-like receptor-4 (TLR4), suggesting inhibition of TLR4-JNK signaling. Moreover, it reduced inflammation-associated IL-6 and MCP-1 mRNA levels in both adipocytes and adipocyte-macrophage system. Our study showed that palmitate treatment led to adipocyte dysfunction and macrophage infiltration; however, AL improved palmitate-induced glucose intolerance and inflammation. These findings suggest that AL may inhibit obesity-induced insulin resistance and improve glucose homeostasis and inflammation in insulin target tissues.
肥胖的特征是巨噬细胞大量浸润脂肪组织。脂肪细胞与巨噬细胞共同引发炎症与胰岛素抵抗之间的相互作用。通过门静脉系统吸收的过量饱和脂肪酸（如棕榈酸）可能会导致葡萄糖不耐受和炎症，进而引发胰岛素抵抗。在本研究中，我们旨在评估从土木香中分离出的倍半萜内酯土木香内酯（AL）在降低棕榈酸诱导的3T3-L1脂肪细胞及脂肪细胞-巨噬细胞共培养体系（3T3-L1-RAW264.7）中的葡萄糖不耐受、脂肪堆积和炎症方面的效力。我们观察到，棕榈酸降低了葡萄糖摄取并增加了脂肪堆积，这表明脂肪细胞功能失调且脂质储存不足。然而，AL处理以剂量依赖的方式逆转了这些变化（P<0.05）。棕榈酸激活了c-Jun氨基末端激酶（JNK）和IκB激酶β/α（IKKβ/α）的磷酸化，并增加了促炎细胞因子（肿瘤坏死因子-α和白细胞介素-6 [IL-6]）和趋化因子（单核细胞趋化蛋白-1 [MCP-1]）的水平。AL处理选择性地降低了与JNK相关的丝裂原活化蛋白激酶途径（JNK和细胞外信号调节激酶磷酸化）。然而，它并未影响脂肪细胞中的NF-κB途径。此外，AL降低了JNK上调因子Toll样受体4（TLR4）的基因表达，表明抑制了TLR4-JNK信号传导。此外，它降低了脂肪细胞和脂肪细胞-巨噬细胞体系中与炎症相关的IL-6和MCP-1 mRNA水平。我们的研究表明，棕榈酸处理导致脂肪细胞功能障碍和巨噬细胞浸润；然而，AL改善了棕榈酸诱导的葡萄糖不耐受和炎症。这些发现表明，AL可能抑制肥胖诱导的胰岛素抵抗，并改善胰岛素靶组织中的葡萄糖稳态和炎症。
