Reduced adiposity and improved insulin sensitivity in obese mice with antisense suppression of 4E-BP2 expression

• Published in: American journal of physiology: endocrinology and metabolism 2008-03, Vol.294 (3), p.E530-E539
• Main Authors: Yu, Xing Xian, Pandey, Sanjay K, Booten, Sheri L, Murray, Susan F, Monia, Brett P, Bhanot, Sanjay
• Format: Article
• Language: English
• Subjects: Adipose Tissue - chemistry; Adiposity - physiology; Animals; Binding sites; Biochemistry; Blood Glucose - analysis; Body fat; Dietary Fats - administration & dosage; Energy Metabolism; Eukaryotes; Eukaryotic Initiation Factors - antagonists & inhibitors; Eukaryotic Initiation Factors - genetics; Eukaryotic Initiation Factors - physiology; Fatty Liver - etiology; Fatty Liver - therapy; Gene expression; Gene Expression - drug effects; Homeostasis; Insulin; Insulin - pharmacology; Liver - chemistry; Male; Mice; Mice, Inbred C57BL; Obesity - physiopathology; Oligonucleotides, Antisense - genetics; Oligonucleotides, Antisense - pharmacology; Proteins; RNA, Messenger - analysis; Transfection; Weight Loss
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00350.2007

Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc., Carlsbad, California Submitted 5 June 2007 ; accepted in final form 9 January 2008 To investigate the possible role of eukaryotic initiation factor 4E-binding protein-2 (4E-BP2) in metabolism and energy homeostasis, high-fat diet-induced obese mice were treated with a 4E-BP2-specific antisense oligonucleotide (ASO) or a control 4E-BP2 ASO at a dose of 25 mg/kg body wt or with saline twice a week for 6 wk. 4E-BP2 ASO treatment reduced 4E-BP2 levels by >75% in liver and white (WAT) and brown adipose (BAT) tissues. Treatment did not change food intake but lowered body weight by 7% and body fat content by 18%. Treatment decreased liver triglyceride (TG) content by >50%, normalized plasma glucose and insulin levels, and reduced glucose excursion during glucose tolerance test. 4E-BP2 ASO-treated mice showed >8.5% increase in metabolic rate, >40% increase in UCP1 levels in BAT, >45% increase in β 3 -adrenoceptor mRNA, and 40–55% decrease in mitochondrial dicarboxylate carrier, fatty acid synthase, and diacylglycerol acyltransferase 2 mRNA levels in WAT. 4E-BP2 ASO-transfected mouse hepatocytes showed an increased fatty acid oxidation rate and a decreased TG synthesis rate. In addition, 4E-BP2 ASO-treated mice demonstrated 60 and 29% decreases in hepatic glucose-6-phosphatase and phospho enol pyruvate carboxykinase mRNA, respectively, implying decreased hepatic glucose output. Furthermore, increased phosphorylation of Akt Ser473 in both liver and fat of 4E-BP2 ASO-treated mice and increased GLUT4 levels in plasma membrane in WAT of the ASO-treated mice were observed, indicating enhanced insulin signaling and increased glucose uptake as a consequence of reduced 4E-BP2 expression. These data demonstrate for the first time that peripheral 4E-BP2 plays an important role in metabolism and energy homeostasis. eukaryotic initiation factor 4E-binding protein-2; antisense oligonucleotide; body weight; metabolic rate; insulin signaling; gene expression Address for reprint requests and other correspondence: X. X. Yu, 1896 Rutherford Rd., Carlsbad, CA 92008 (e-mail: xyu{at}isisph.com )