Reduction of JNK1 expression with antisense oligonucleotide improves adiposity in obese mice

Department of Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, California Submitted 28 September 2007 ; accepted in final form 1 June 2008 To investigate the role of JNK1 in metabolism, male ob / ob and diet-induced obese mice were treated with a JNK1-specific antisense oligonucleotide (ASO) or control ASO at 25 mg/kg or saline twice/wk for 6 and 7 wk, respectively. JNK1 ASO reduced JNK1 mRNA and activity by 65–95% in liver and fat tissues in both models. Compared with controls, treatment with JNK1 ASO did not change food intake but lowered body weight, fat pad weight, and whole body fat content. The treatment increased metabolic rate. In addition, the treatment markedly reduced plasma cholesterol levels and improved liver steatosis and insulin sensitivity. These positive observations were accompanied by the following changes: 1 ) increased mRNA levels of AR-β 3 and UCP1 by >60% in BAT, 2 ) reduced mRNA levels of ACC1, ACC2, FAS, SCD1, DGAT1, DGAT2, and RBP4 by 30–60% in WAT, and 3 ) reduced mRNA levels of ACC1, FAS, G-6-Pase, and PKC by 40–70% and increased levels of UCP2 and PPAR by more than twofold in liver. JNK1 ASO-treated mice demonstrated reduced levels of pIRS-1 Ser 302 and pIRS-1 Ser 307 and increased levels of pAkt Ser 473 in liver and fat in response to insulin. JNK1 ASO-transfected mouse hepatocytes showed decreased rates of de novo sterol and fatty acid synthesis and an increased rate of fatty acid oxidation. These results indicate that inhibition of JNK1 expression in major peripheral tissues can improve adiposity via increasing fuel combustion and decreasing lipogenesis and could therefore provide clinical benefit for the treatment of obesity and related metabolic abnormalities. insulin sensitivity; metabolic rate; gene expression; antisense Address for reprint requests and other correspondence: X. X. Yu, 1896 Rutherford Rd., Carlsbad, CA 92008 (e-mail: xyu{at}isisph.com )