title: Loss of FKBP5 impedes adipocyte differentiation under both normoxia and hypoxic stress.
abstract: FK506-binding protein 51 (FKBP51) is one of the most important regulators in the GR-mediated stress response, and we previously demonstrated that loss of FKBP5 arrests adipogenesis and renders mice resistant to diet-induced obesity (DIO). However, the exact role of FKBP5 in the process of adipocyte differentiation under hypoxic conditions (the common microenvironment where adipocytes reside in obese individuals) is still unclear. Here, by isolating and culturing WT- and Fkbp5-knockout mouse embryonic fibroblasts (MEFs), and treat them at normal oxygen environment (21% O2, nomorxia) or low oxygen environment (5% O2, hypoxia). Enhanced adipogenesis were observed at hypoxia when compared to normal oxygen environment. The loss of FKBP5 significantly prevents the adipogenesis from KO MEFs under nomorxia condition, with subtle enhancement of adipogenesis at hypoxia condition, which is similar as observed in WT-MEFs at hypoxia condition but with obvious enhancement of adipogenesis. Importantly, the protein level of FKBP5 reduced in undifferentiated MEFs under acute hypoxic stress (24 h), but drastically increased during the mid-late stage of adipocyte (Day 6) differentiation from WT-MEFs under chronic hypoxia. Furthermore, we find under normal and hypoxic conditions that FKBP5 deletion alters the expression profile of adipogenesis-related genes, including those involved in lipogenesis, lipolysis, and energy metabolism, which partially explains the compromised adipocyte differentiation in FKBP51-KO MEFs. Taken together, our findings identify a novel role of FKBP5 in hypoxia-regulated adipogenesis, and provide a candidate for anti-obesity strategies targeting FKBP51.
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Qiu
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Yuxue
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Deng
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Kent
authors.initials: K
authors.lastname: Williams
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: tliang@iu.edu.
authors.forename: Tiebing
authors.initials: T
authors.lastname: Liang
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China. Electronic address: wyong@cnilas.org.
authors.forename: Weidong
authors.initials: W
authors.lastname: Yong
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics; D052242:Adiponectin / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D018955:CD36 Antigens / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D022021:Tacrolimus Binding Proteins / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D000071256:Uncoupling Protein 1 / Q000235:genetics; D000099159:Tacrolimus Binding Protein 5
chemical_list: D052242:Adiponectin; D018955:CD36 Antigens; D022021:Tacrolimus Binding Proteins; D000071256:Uncoupling Protein 1; D000099159:Tacrolimus Binding Protein 5; C000604372:Ucp1 protein, mouse
keywords: Adipogenesis; FKBP5; Glucocorticoid receptor; Hypoxic stress; Mouse embryonic fibroblasts