title: Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice.
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.
authors.affiliation: Département d'Endocrinologie, Institut Cochin, Métabolisme et Cancer, 24 rue du Faubourg St. Jacques, Paris 75014, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Dentin
authors.forename: Fadila
authors.initials: F
authors.lastname: Benhamed
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hainault
authors.forename: Véronique
authors.initials: V
authors.lastname: Fauveau
authors.forename: Fabienne
authors.initials: F
authors.lastname: Foufelle
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.forename: Jean
authors.initials: J
authors.lastname: Girard
authors.forename: Catherine
authors.initials: C
authors.lastname: Postic
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001786:Blood Glucose / Q000032:analysis; D004040:Dietary Carbohydrates / Q000008:administration & dosage; D015536:Down-Regulation / Q000235:genetics; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005234:Fatty Liver / Q000209:etiology* / Q000235:genetics / Q000517:prevention & control; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000032:analysis; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology*; D020738:Leptin / Q000172:deficiency; D008055:Lipids / Q000032:analysis / Q000096:biosynthesis; D008099:Liver / Q000737:chemistry* / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000737:chemistry; D009687:Nuclear Proteins / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D009765:Obesity / Q000150:complications* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D014162:Transfection; D014280:Triglycerides / Q000097:blood
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001786:Blood Glucose; D004040:Dietary Carbohydrates; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D020738:Leptin; D008055:Lipids; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; D014280:Triglycerides; D006003:Glycogen; D005947:Glucose