Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea.
Healthy Aging Korean Medical Research Center, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea.
Int J Mol Sci. 2018 Mar 23;19(4):968. doi: 10.3390/ijms19040968.
Activation of the hepatic cannabinoid type 1 receptor (CB1R) induces insulin resistance and gluconeogenesis via endoplasmic reticulum (ER) stress, thereby contributing to hyperglycemia. Gomisin N (GN) is a phytochemical derived from . In the current study, we investigated the inhibitory effects of GN on hepatic CB1R-mediated insulin resistance and gluconeogenesis in 2-arachidonoylglycerol (AG; an agonist of CB1R)-treated HepG2 cells and in high-fat diet (HFD)-induced obese mice. Treatment with 2-AG induced the expression of ER stress markers, serine/threonine phosphatase , , and ceramide synthesis genes, but reduced the expression of ceramide degradation genes in HepG2 cells. However, GN reversed 2-AG-mediated effects and improved the 2-AG-mediated impairment of insulin signaling. Furthermore, GN inhibited 2-AG-induced intracellular triglyceride accumulation and glucose production in HepG2 cells by downregulation of lipogenesis and gluconeogenesis genes, respectively. In vivo, GN administration to HFD obese mice reduced the HFD-induced increase in fasting blood glucose and insulin levels, which was accompanied with downregulation of HFD-induced expression of CB1R, ER stress markers, ceramide synthesis gene, and gluconeogenesis genes in the livers of HFD obese mice. These findings demonstrate that GN protects against hepatic CB1-mediated impairment of insulin signaling and gluconeogenesis, thereby contributing to the amelioration of hyperglycemia.
肝大麻素受体 1 型（CB1R）的激活会通过内质网（ER）应激诱导胰岛素抵抗和糖异生，从而导致高血糖。戈米辛 N（GN）是一种源自. 在本研究中，我们研究了 GN 对 2-花生四烯酸甘油（AG；CB1R 激动剂）处理的 HepG2 细胞和高脂肪饮食（HFD）诱导肥胖小鼠中肝 CB1R 介导的胰岛素抵抗和糖异生的抑制作用。AG 处理诱导 ER 应激标志物、丝氨酸/苏氨酸磷酸酶 和神经酰胺合成基因的表达，但降低了神经酰胺降解基因的表达。然而，GN 逆转了 2-AG 介导的作用，并改善了 2-AG 介导的胰岛素信号转导损伤。此外，GN 通过下调脂肪生成和糖异生基因，分别抑制了 2-AG 诱导的 HepG2 细胞内三酰甘油积累和葡萄糖生成。在体内，GN 给药于 HFD 肥胖小鼠可降低 HFD 诱导的空腹血糖和胰岛素水平升高，同时伴随着 HFD 诱导的 CB1R、ER 应激标志物、神经酰胺合成基因和糖异生基因在 HFD 肥胖小鼠肝脏中的表达下调。这些发现表明，GN 可防止肝 CB1 介导的胰岛素信号转导和糖异生受损，从而有助于改善高血糖。
