Liver-Specific Inhibition of ChREBP Improves Hepatic Steatosis and Insulin Resistance in ob/ob Mice
Renaud Dentin 1 ,
Fadila Benhamed 1 ,
Isabelle Hainault 2 ,
Véronique Fauveau 3 ,
Fabienne Foufelle 2 ,
Jason R.B. Dyck 4 ,
Jean Girard 1 and
Catherine Postic 1
1 Institut Cochin, Département d’Endocrinologie, Métabolisme et Cancer, Institut National de la Santé et de la Recherche Médicale
(INSERM) U567, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Université René Descartes, Paris,
France;
2 Unité INSERM U671, Centre de Recherches Biomédicales des Cordeliers, Université Paris VI, Paris, France;
3 Plate-Forme de Micro-Chirurgie de l’Institut Cochin, Paris, France;
4 Cardiovascular Research Group, Department of Pediatrics and Pharmacology, Faculty of Medicine and Dentistry, University of
Alberta, Alberta, Canada
Address correspondence and reprint requests to Catherine Postic, Institut Cochin, Département d’Endocrinologie, Métabolisme
et Cancer, 24 rue du Faubourg St. Jacques, Paris 75014, France. E-mail: postic{at}cochin.inserm.fr
Abstract
Obesity is a metabolic disorder often associated with type 2 diabetes, insulin resistance, and hepatic steatosis. Leptin-deficient
( ob/ob ) mice are a well-characterized mouse model of obesity in which increased hepatic lipogenesis is thought to be responsible
for the phenotype of insulin resistance. We have recently demonstrated that carbohydrate responsive element–binding protein
(ChREBP) plays a key role in the control of lipogenesis through the transcriptional regulation of lipogenic genes, including
acetyl-CoA carboxylase and fatty acid synthase. The present study reveals that ChREBP gene expression and ChREBP nuclear protein
content are significantly increased in liver of ob/ob mice. To explore the involvement of ChREBP in the physiopathology of hepatic steatosis and insulin resistance, we have developed
an adenovirus-mediated RNA interference technique in which short hairpin RNAs (shRNAs) were used to inhibit ChREBP expression
in vivo. Liver-specific inhibition of ChREBP in ob/ob mice markedly improved hepatic steatosis by specifically decreasing lipogenic rates. Correction of hepatic steatosis also
led to decreased levels of plasma triglycerides and nonesterified fatty acids. As a consequence, insulin signaling was improved
in liver, skeletal muscles, and white adipose tissue, and overall glucose tolerance and insulin sensitivity were restored
in ob/ob mice after a 7-day treatment with the recombinant adenovirus expressing shRNA against ChREBP. Taken together, our results
demonstrate that ChREBP is central for the regulation of lipogenesis in vivo and plays a determinant role in the development
of the hepatic steatosis and of insulin resistance in ob/ob mice.
ACC, acetyl-CoA carboxylase
Ad-GFP, GFP adenovirus
Ad-shChREBP, recombinant adenovirus expressing short hairpin RNA against ChREBP
ChREBP, carbohydrate responsive element–binding protein
ERK, extracellular signal–related kinase
FAS, fatty acid synthase
G6Pase, glucose 6-phosphatase
GFP, green fluorescent protein
GK, glucokinase
GPAT, glyceraldehyde 3-phosphate acyltransferase
GSK, glycogen synthase kinase
MAPK, mitogen-activated protein kinase
NAFLD, nonalcoholic fatty liver disease
NEFA, nonesterified fatty acid
shChREBP, short hairpin RNA against ChREBP
shRNA, short hairpin RNA
SCD, stearoyl-CoA desaturase
SREBP, sterol regulatory element–binding protein
Footnotes
Additional information on this article can be found in an online appendix at http://diabetes.diabetesjournals.org .
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted May 8, 2006.
Received February 10, 2006.
DIABETES...

Liver-Specific Inhibition of ChREBP Improves Hepatic Steatosis and Insulin Resistance in ob/ob Mice

10.2337/db06-0200