RNase L controls terminal adipocyte differentiation, lipids storage and insulin sensitivity via CHOP10 mRNA regulation

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 end...

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Bibliographic Details
Published in:	Cell death and differentiation Vol. 19; no. 9; pp. 1470 - 1481
Main Authors:	Fabre, O, Salehzada, T, Lambert, K, Boo Seok, Y, Zhou, A, Mercier, J, Bisbal, C
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-09-2012 Nature Publishing Group
Subjects:	631/136/142 631/45/500 631/45/607/1164 Adipocytes Adipocytes - cytology Adipocytes - metabolism adipogenesis Adipogenesis - physiology Adipose tissue Animals Apoptosis Biochemistry Biomedical and Life Sciences Body fat CCAAT/enhancer-binding protein Cell Biology Cell Cycle Analysis Cell death Cell Differentiation - physiology Differentiation Down-Regulation - physiology Embryo fibroblasts Endoribonucleases - genetics Endoribonucleases - metabolism Gene expression Glucose Glucose - genetics Glucose - metabolism Human health and pathology Insulin Insulin resistance Insulin Resistance - physiology Kidney Life Sciences Lipid Metabolism - physiology Lipids Liver Metabolism Mice Mice, Knockout mRNA Obesity Original Paper Preadipocytes Proteins Ribonuclease ribonuclease A ribonuclease L RNA Stability - physiology RNA, Messenger - genetics RNA, Messenger - metabolism siRNA Stem Cells Tissues and Organs Transcription Factor CHOP - biosynthesis Transcription Factor CHOP - genetics France adipogenesis CHOP10 RNase L insulin response
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	1350-9047 1476-5403
DOI:	10.1038/cdd.2012.23