Qinyue Guo1, Lin Xu2, Huixia Li3, Hongzhi Sun3, Shufang Wu4, Bo Zhou5. 1. Department of Respiratory, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Street, Xi'an, Shaanxi 710061, China; Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Street, Xi'an, Shaanxi 710061, China. 2. Department of Endocrinology, The Affiliated Guangren Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China. 3. Key Laboratory of Environment and Genes Related to Diseases, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China. 4. Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China. Electronic address: wushufangxian@126.com. 5. Department of Respiratory, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Street, Xi'an, Shaanxi 710061, China. Electronic address: zb_bob@stu.xjtu.edu.cn.
Abstract
BACKGROUND: 4-phenyl butyric acid (4-PBA) has been considered as a key regulator of insulin resistance in obesity. However the mechanism of 4-PBA involved in insulin resistance remains elusive. METHODS: We evaluated the effect of 4-PBA on abnormal autophagy and endoplasmic reticulum (ER) stress in obese mice. 4-PBA was administered in obese mice and adipocyte models, and metabolic parameters, autophagy markers, ER stress indicators, Akt/mTOR signaling and insulin signaling molecular were assessed. RESULTS: 4-PBA treatment not only reversed autophagic dysfunction and ER stress, but also improved impaired insulin signaling in tunicamycin-induced adipocytes, and 4-PBA also inhibited activated ER stress and elevated insulin sensitivity in adipocytes with Atg7 siRNA. Additionally, administration of 4-PBA improves glucose tolerance and insulin sensitivity in obese mice via regulating abnormal autophagy and ER stress in adipose tissue. The protective effects of 4-PBA were nullified by suppression of Akt and mTOR in adipocytes, suggesting that 4-PBA inhibits autophagy and restores insulin sensitivity via Akt/mTOR signaling partially. CONCLUSIONS: 4-PBA reverses autophagic dysfunction and improves insulin sensitivity in adipose tissue of obese mice via Akt/mTOR signaling partly, which could be regarded as novel opportunities for treatment of insulin resistance.
BACKGROUND:4-phenyl butyric acid (4-PBA) has been considered as a key regulator of insulin resistance in obesity. However the mechanism of 4-PBA involved in insulin resistance remains elusive. METHODS: We evaluated the effect of 4-PBA on abnormal autophagy and endoplasmic reticulum (ER) stress in obesemice. 4-PBA was administered in obesemice and adipocyte models, and metabolic parameters, autophagy markers, ER stress indicators, Akt/mTOR signaling and insulin signaling molecular were assessed. RESULTS:4-PBA treatment not only reversed autophagic dysfunction and ER stress, but also improved impaired insulin signaling in tunicamycin-induced adipocytes, and 4-PBA also inhibited activated ER stress and elevated insulin sensitivity in adipocytes with Atg7 siRNA. Additionally, administration of 4-PBA improves glucose tolerance and insulin sensitivity in obesemice via regulating abnormal autophagy and ER stress in adipose tissue. The protective effects of 4-PBA were nullified by suppression of Akt and mTOR in adipocytes, suggesting that 4-PBA inhibits autophagy and restores insulin sensitivity via Akt/mTOR signaling partially. CONCLUSIONS:4-PBA reverses autophagic dysfunction and improves insulin sensitivity in adipose tissue of obesemice via Akt/mTOR signaling partly, which could be regarded as novel opportunities for treatment of insulin resistance.
Authors: Ashraf U Nissar; Love Sharma; Malik A Mudasir; Lone A Nazir; Sheikh A Umar; Parduman R Sharma; Ram A Vishwakarma; Sheikh A Tasduq Journal: J Lipid Res Date: 2017-06-27 Impact factor: 5.922
Authors: Ivan Duran; Jennifer Zieba; Fabiana Csukasi; Jorge H Martin; Davis Wachtell; Maya Barad; Brian Dawson; Bohumil Fafilek; Christina M Jacobsen; Catherine G Ambrose; Daniel H Cohn; Pavel Krejci; Brendan H Lee; Deborah Krakow Journal: J Bone Miner Res Date: 2022-01-28 Impact factor: 6.390