Reduced adiposity and improved insulin sensitivity in obese mice with antisense suppression of 4E-BP2 expression.
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 approximately 7% and body fat content by approximately 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 beta(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 approximately 60 and 29% decreases in hepatic glucose-6-phosphatase and phosphoenolpyruvate 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.
Yu
Xing Xian
XX
Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc., Carlsbad, California 92008, USA. xyu@isisph.com
Pandey
Sanjay K
SK
Booten
Sheri L
SL
Murray
Susan F
SF
Monia
Brett P
BP
Bhanot
Sanjay
S
D000273:Adipose Tissue / Q000737:chemistry; D050154:Adiposity / Q000502:physiology*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D004041:Dietary Fats / Q000008:administration & dosage; D004734:Energy Metabolism; D039642:Eukaryotic Initiation Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D005234:Fatty Liver / Q000209:etiology / Q000628:therapy; D015870:Gene Expression / Q000187:drug effects; D006706:Homeostasis; D007328:Insulin / Q000494:pharmacology*; D008099:Liver / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000503:physiopathology*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D014162:Transfection; D015431:Weight Loss
D001786:Blood Glucose; D004041:Dietary Fats; C491255:Eif4ebp2 protein, mouse; D039642:Eukaryotic Initiation Factors; D007328:Insulin; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger