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

Abstract

S. Reduced adiposity and improved insulin sensitivity in obese mice with antisense suppression of 4E-BP2 expression. Am J Physiol Endocrinol Metab 294: E530-E539, 2008. First published January 15, 2008 doi:10.1152/ajpendo.00350.2007To 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 Ͼ75% in liver and white (WAT) and brown adipose (BAT) tissues. Treatment did not change food intake but lowered body weight by ϳ7% and body fat content by ϳ18%. Treatment decreased liver triglyceride (TG) content by Ͼ50%, normalized plasma glucose and insulin levels, and reduced glucose excursion during glucose tolerance test. 4E-BP2 ASO-treated mice showed Ͼ8.5% increase in metabolic rate, Ͼ40% increase in UCP1 levels in BAT, Ͼ45% increase in ␤ 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 ϳ60 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 ASOtreated 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 THE PREVALENCE OF OBESITY has been steadily increasing over the last decade and has become a world-wide health problem. Obesity is the primary risk factor associated with development of a cluster of metabolic disorders, including type 2 diabetes, fatty liver, dyslipidemia, and cardiovascular disease. However, effective drugs for the treatment of obesity and associated disorders are largely elusive. Therefore, an urgent need continues to exist for identifying new therapeutic targets and drug platforms for these disorders.Recent studies indicate that eukaryotic translation initiation factor 4E (eIF4E)-binding proteins (4E-BPs) may play an important role in the regulation of fat metabolism. 4E-BPs inhibit 5Ј cap-dependent translation initiation through sequestering eIF4E from the eIF4F complex (17, 25). Three 4E-BPs, 4E-BP1, -2, and -3, have been found in mammals. 4E-BP1 is highly expressed in fat and muscle, whereas 4E-BP2 is ubiquitous...

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