title: RNase L controls terminal adipocyte differentiation, lipids storage and insulin sensitivity via CHOP10 mRNA regulation.
abstract: Adipose tissue structure is altered during obesity, leading to deregulation of whole-body metabolism. Its function depends on its structure, in particular adipocytes number and differentiation stage. To better understand the mechanisms regulating adipogenesis, we have investigated the role of an endoribonuclease, endoribonuclease L (RNase L), using wild-type and RNase L-knockout mouse embryonic fibroblasts (RNase L(-/-)-MEFs). Here, we identify C/EBP homologous protein 10 (CHOP10), a dominant negative member of the CCAAT/enhancer-binding protein family, as a specific RNase L target. We show that RNase L is associated with CHOP10 mRNA and regulates its stability. CHOP10 expression is conserved in RNase L(-/-)-MEFs, maintaining preadipocyte state while impairing their terminal differentiation. RNase L(-/-)-MEFs have decreased lipids storage capacity, insulin sensitivity and glucose uptake. Expression of ectopic RNase L in RNase L(-/-)-MEFs triggers CHOP10 mRNA instability, allowing increased lipids storage, insulin response and glucose uptake. Similarly, downregulation of CHOP10 mRNA with CHOP10 siRNA in RNase L(-/-)-MEFs improves their differentiation in adipocyte. In vivo, aged RNase L(-)/(-) mice present an expanded adipose tissue, which, however, is unable to correctly store lipids, illustrated by ectopic lipids storage in the liver and in the kidney. These findings highlight RNase L as an essential regulator of adipogenesis via the regulation of CHOP10 mRNA.
authors.affiliation: U1046 Physiologie et médecine expérimentale du coeur et des muscles-INSERM-Université Montpellier 1-Université Montpellier 2, Montpellier, France.
authors.forename: O
authors.initials: O
authors.lastname: Fabre
authors.forename: T
authors.initials: T
authors.lastname: Salehzada
authors.forename: K
authors.initials: K
authors.lastname: Lambert
authors.forename: Y
authors.initials: Y
authors.lastname: Boo Seok
authors.forename: A
authors.initials: A
authors.lastname: Zhou
authors.forename: J
authors.initials: J
authors.lastname: Mercier
authors.forename: C
authors.initials: C
authors.lastname: Bisbal
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D050156:Adipogenesis / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D015536:Down-Regulation / Q000502:physiology; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D020871:RNA Stability / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C497250:Ddit3 protein, mouse; D012333:RNA, Messenger; D051742:Transcription Factor CHOP; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D005947:Glucose