title: DNAJB3/HSP-40 cochaperone improves insulin signaling and enhances glucose uptake in vitro through JNK repression.
abstract: Heat shock response (HSR) is an essential host-defense mechanism that is dysregulated in obesity-induced insulin resistance and type 2 diabetes (T2D). Our recent data demonstrated that DNAJB3 was downregulated in obese human subjects and showed negative correlation with inflammatory markers. Nevertheless, DNAJB3 expression pattern in diabetic subjects and its mode of action are not yet known. In this study, we showed reduction in DNAJB3 transcript and protein levels in PBMC and subcutaneous adipose tissue of obese T2D compared to obese non-diabetic subjects. Overexpression of DNAJB3 in HEK293 and 3T3-L1 cells reduced JNK, IRS-1 Ser-307 phosphorylation and enhanced Tyr-612 phosphorylation suggesting an improvement in IRS-1 signaling. Furthermore, DNAJB3 mediated the PI3K/AKT pathway activation through increasing AKT and AS160 phosphorylation. AS160 mediates the mobilization of GLUT4 transporter to the cell membrane and thereby improves glucose uptake. Using pre-adipocytes cells we showed that DNAJB3 overexpression caused a significant increase in the glucose uptake, possibly through its phosphorylation of AS160. In summary, our results shed the light on the possible role of DNAJB3 in improving insulin sensitivity and glucose uptake through JNK repression and suggest that DNAJB3 could be a potential target for therapeutic treatment of obesity-induced insulin resistance.
authors.affiliation: Biochemistry and Molecular Biology unit, Dasman Diabetes Institute, Kuwait.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abu-Farha
authors.affiliation: Biochemistry and Molecular Biology unit, Dasman Diabetes Institute, Kuwait.
authors.forename: Preethi
authors.initials: P
authors.lastname: Cherian
authors.affiliation: Biochemistry and Molecular Biology unit, Dasman Diabetes Institute, Kuwait.
authors.forename: Irina
authors.initials: I
authors.lastname: Al-Khairi
authors.affiliation: Biochemistry and Molecular Biology unit, Dasman Diabetes Institute, Kuwait.
authors.forename: Ali
authors.initials: A
authors.lastname: Tiss
authors.affiliation: Biochemistry and Molecular Biology unit, Dasman Diabetes Institute, Kuwait.
authors.forename: Abdelkrim
authors.initials: A
authors.lastname: Khadir
authors.affiliation: Biochemistry and Molecular Biology unit, Dasman Diabetes Institute, Kuwait.
authors.forename: Sina
authors.initials: S
authors.lastname: Kavalakatt
authors.affiliation: Biochemistry and Molecular Biology unit, Dasman Diabetes Institute, Kuwait.
authors.forename: Samia
authors.initials: S
authors.lastname: Warsame
authors.affiliation: Diabetes Research Center, Qatar Biomedical Research Institute, Education City, Doha, Qatar.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Dehbi
authors.affiliation: Biochemistry and Molecular Biology unit, Dasman Diabetes Institute, Kuwait.
authors.forename: Kazem
authors.initials: K
authors.lastname: Behbehani
authors.affiliation: Biochemistry and Molecular Biology unit, Dasman Diabetes Institute, Kuwait.
authors.forename: Jehad
authors.initials: J
authors.lastname: Abubaker
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D057809:HEK293 Cells; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D015398:Signal Transduction
chemical_list: C000610086:DNAJB3 protein, human; D050956:HSP40 Heat-Shock Proteins; D007328:Insulin; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose