title: The reciprocal interaction between autophagic dysfunction and ER stress in adipose insulin resistance.
abstract: Autophagy, a predominantly cytoprotective process, is an important regulator in diabetic metabolism and endoplasmic reticulum (ER) stress responses. However, the interaction and biological significance between autophagic imbalance and ER stress involved in insulin resistance remain not fully elucidated. In the present study, when compared with normal glucose tolerance (NGT) subjects, enhanced ER stress and pronounced protein and mRNA levels of the autophagic genes such as Atg7, LC3A, and LC3B were evident in adipose tissue of patients with type 2 diabetes. An increased number of autophagosomes and elevated autophagy flux in adipose explants incubated with lysomoal inhibitor were also observed in type 2 diabetes. In addition, adipocytes differentiation was significantly repressed by exogenous ER stress and defective autophagy in vitro. Tunicamycin-induced ER stress in adipocytes can trigger autophagic response and insulin insensitivity that was partially attributed to the upregulation of IRE1-JNK pathway, whereas autophagy deficiency resulted in ER stress and impaired insulin signaling, further supporting the crucial roles of autophagy in ER stress and insulin resistance. Moreover, disturbance of autophagy and insulin sensitivity induced by tunicamycin can be effectively corrected by the addition of osteocalcin in an NFκB-dependent manner in vitro. In conclusion, our results demonstrated a reciprocal functional interaction among autophagy, ER stress, and insulin signaling in adipose tissue of type 2 diabetes and adipocytes, supporting an adaptive role of autophagy-dependent mechanism in response to ER stress-induced insulin resistance in type 2 diabetes.
authors.affiliation: First Affiliated Hospital of Medical School of Xi'an Jiaotong University; Key Laboratory of Environment and Genes Related to Diseases; Ministry of Education; Medical School of Xi'an Jiaotong University; Xi'an, Shaanxi, China.
authors.forename: Huixia
authors.initials: H
authors.lastname: Li
authors.affiliation: First Affiliated Hospital of Medical School of Xi'an Jiaotong University; Key Laboratory of Environment and Genes Related to Diseases; Ministry of Education; Medical School of Xi'an Jiaotong University; Xi'an, Shaanxi, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
authors.affiliation: First Affiliated Hospital of Medical School of Xi'an Jiaotong University; Key Laboratory of Environment and Genes Related to Diseases; Ministry of Education; Medical School of Xi'an Jiaotong University; Xi'an, Shaanxi, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: First Affiliated Hospital of Medical School of Xi'an Jiaotong University; Key Laboratory of Environment and Genes Related to Diseases; Ministry of Education; Medical School of Xi'an Jiaotong University; Xi'an, Shaanxi, China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Liu
authors.affiliation: First Affiliated Hospital of Medical School of Xi'an Jiaotong University; Key Laboratory of Environment and Genes Related to Diseases; Ministry of Education; Medical School of Xi'an Jiaotong University; Xi'an, Shaanxi, China.
authors.forename: Weijin
authors.initials: W
authors.lastname: Zang
authors.affiliation: First Affiliated Hospital of Medical School of Xi'an Jiaotong University; Key Laboratory of Environment and Genes Related to Diseases; Ministry of Education; Medical School of Xi'an Jiaotong University; Xi'an, Shaanxi, China.
authors.forename: Shufang
authors.initials: S
authors.lastname: Wu
authors.affiliation: First Affiliated Hospital of Medical School of Xi'an Jiaotong University; Key Laboratory of Environment and Genes Related to Diseases; Ministry of Education; Medical School of Xi'an Jiaotong University; Xi'an, Shaanxi, China.
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Sun
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D050154:Adiposity / Q000187:drug effects / Q000502:physiology*; D000328:Adult; D000368:Aged; D001343:Autophagy / Q000502:physiology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D004722:Endoribonucleases / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D015675:Osteocalcin / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D016328:NF-kappa B; D015675:Osteocalcin; D014415:Tunicamycin; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D048670:MAP Kinase Kinase 4; D004722:Endoribonucleases
keywords: ER stress; adipose tissue; autophagy; insulin resistance