4-PBA reverses autophagic dysfunction and improves insulin sensitivity in adipose tissue of obese mice via Akt/mTOR signaling.
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.



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.



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.



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.
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.
Qinyue
Q
Guo
Department of Endocrinology, The Affiliated Guangren Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China.
Lin
L
Xu
Key Laboratory of Environment and Genes Related to Diseases, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
Huixia
H
Li
Key Laboratory of Environment and Genes Related to Diseases, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
Hongzhi
H
Sun
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China. Electronic address: wushufangxian@126.com.
Shufang
S
Wu
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.
Bo
B
Zhou
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002082:Butylamines / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
C121358:4-phenylbutylamine; D002082:Butylamines; D007328:Insulin; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose
4-PBA; Akt/mTOR signaling; Autophagy; Insulin resistance