Jie Yang1, Jing Leng1, Jing-Jing Li1, Jing-fu Tang2, Yi Li1, Bao-Lin Liu1, Xiao-Dong Wen3. 1. State Key Laboratory of Natural Medicines, Department of Chinese Medicines Analysis, China Pharmaceutical University, Nanjing 210009, People's Republic of China. 2. Shanghai Hua Yu Chinese Herbs Co., Ltd, People's Republic of China. 3. State Key Laboratory of Natural Medicines, Department of Chinese Medicines Analysis, China Pharmaceutical University, Nanjing 210009, People's Republic of China. Electronic address: xiaodongwen123@126.com.
Abstract
BACKGROUND: Adipose tissue inflammation is tightly associated with the development of insulin resistance. Corosolic acid (CRA), a natural triterpenoid, is well known as "phyto-insulin" due to its insulin-like activities. However, its underlying mechanism remains unknown. PURPOSE: In this study, we investigated the mechanisms of CRA on improving insulin resistance both in vivo and in vitro. METHODS: C57BL/6 mice were fed with normal diet, high-fat diet (HFD) or HFD with CRA, respectively. General biochemical parameters in blood and glucose intolerance in mice were assayed. Meanwhile, proinflammatory cytokines and macrophage infiltrations in adipose tissues were analyzed by real-time PCR and immunohistochemical staining. The effects of CRA on insulin signaling transduction and AMPK activity in adipose tissues were investigated by western blot. Furthermore, the effects of CRA on AMPK were confirmed on 3T3-L1 cells by using both AMPK inhibitor and AMPKα1/2-specific siRNA RESULTS: CRA attenuated hyperlipidemia, improved insulin sensitivity and glucose intolerance in mice. Meanwhile, it alleviated inflammation in adipose tissues, demonstrated by the suppression of IKKβ phosphorylation and down-regulation of gene expressions of proinflammatory cytokines. Histological analysis revealed that CRA attenuated macrophage infiltrations into adipose tissue. It also improved insulin signaling transduction by modification of Ser/Thr phosphorylation of IRS-1 and downstream Akt, thereby improved insulin sensitivity in HFD-fed mice. Furthermore, CRA regulated AMPK activation in a LKB1-dependent manner. AMPKα knockdown in adipocytes abolished the inhibitory effects of CRA on IKKβ and IRS-1 serine phosphorylation, indicating that CRA inhibited inflammation and ameliorated insulin resistance via AMPK activation. CONCLUSIONS: CRA inhibited inflammation with improvement in adipose tissue dysfunction and ameliorated insulin resistance in an AMPK-dependent manner.
BACKGROUND: Adipose tissue inflammation is tightly associated with the development of insulin resistance. Corosolic acid (CRA), a natural triterpenoid, is well known as "phyto-insulin" due to its insulin-like activities. However, its underlying mechanism remains unknown. PURPOSE: In this study, we investigated the mechanisms of CRA on improving insulin resistance both in vivo and in vitro. METHODS: C57BL/6 mice were fed with normal diet, high-fat diet (HFD) or HFD with CRA, respectively. General biochemical parameters in blood and glucose intolerance in mice were assayed. Meanwhile, proinflammatory cytokines and macrophage infiltrations in adipose tissues were analyzed by real-time PCR and immunohistochemical staining. The effects of CRA on insulin signaling transduction and AMPK activity in adipose tissues were investigated by western blot. Furthermore, the effects of CRA on AMPK were confirmed on 3T3-L1 cells by using both AMPK inhibitor and AMPKα1/2-specific siRNA RESULTS:CRAattenuated hyperlipidemia, improved insulin sensitivity and glucose intolerance in mice. Meanwhile, it alleviated inflammation in adipose tissues, demonstrated by the suppression of IKKβ phosphorylation and down-regulation of gene expressions of proinflammatory cytokines. Histological analysis revealed that CRA attenuated macrophage infiltrations into adipose tissue. It also improved insulin signaling transduction by modification of Ser/Thr phosphorylation of IRS-1 and downstream Akt, thereby improved insulin sensitivity in HFD-fed mice. Furthermore, CRA regulated AMPK activation in a LKB1-dependent manner. AMPKα knockdown in adipocytes abolished the inhibitory effects of CRA on IKKβ and IRS-1serine phosphorylation, indicating that CRA inhibited inflammation and ameliorated insulin resistance via AMPK activation. CONCLUSIONS:CRA inhibited inflammation with improvement in adipose tissue dysfunction and ameliorated insulin resistance in an AMPK-dependent manner.
Authors: Angela Ladurner; Martin Zehl; Ulrike Grienke; Christoph Hofstadler; Nadina Faur; Fátima C Pereira; David Berry; Verena M Dirsch; Judith M Rollinger Journal: Front Pharmacol Date: 2017-07-17 Impact factor: 5.810