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

• Published in: Diabetes (New York, N.Y.) Vol. 55; no. 8; pp. 2159 - 2170
• Main Authors: DENTIN, Renaud, BENHAMED, Fadila, HAINAULT, Isabelle, FAUVEAU, Véronique, FOUFELLE, Fabienne, DYCK, Jason R. B, GIRARD, Jean, POSTIC, Catherine
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.08.2006
• Subjects: Adenovirus; Adenoviruses; Adipose Tissue - metabolism; Animals; Biological and medical sciences; Blood Glucose - analysis; Body fat; Carbohydrates; Care and treatment; Diabetes; Diabetes mellitus; Diabetes. Impaired glucose tolerance; Dietary Carbohydrates - administration & dosage; Down-Regulation - genetics; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty acids; Fatty Acids, Nonesterified - blood; Fatty Liver - etiology; Fatty Liver - genetics; Fatty Liver - prevention & control; Gastroenterology. Liver. Pancreas. Abdomen; Gene expression; Glucose; Glucose - metabolism; Glucose Tolerance Test; Glycogen - analysis; Health aspects; Insulin - physiology; Insulin resistance; Insulin Resistance - physiology; Kinases; Leptin - deficiency; Life Sciences; Lipids - analysis; Lipids - biosynthesis; Liver - chemistry; Liver - metabolism; Liver diseases; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Metabolism; Mice; Mice, Obese; Muscle, Skeletal - chemistry; Nuclear Proteins - analysis; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - genetics; Obesity; Obesity - complications; Obesity - genetics; Other diseases. Semiology; Pathogenesis; Prevention; Proteins; RNA, Messenger - analysis; RNA, Small Interfering - genetics; Signal Transduction; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transfection; Triglycerides - blood; France; Endocrinopathy; Vertebrata; Mammalia; Fatty liver; Mouse; Digestive system; Animal; Diabetes mellitus; Rodentia; Hepatic disease; Insulin resistance; Inhibition
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db06-0200

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