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- Title
Reduction of JNK1 Expression Lowers Adiposity and Improves Insulin Sensitivity in Diet-Induced Obese Mice.
- Authors
Murray, Susan F.; Watts, Lynnetta M.; Booten, Sheri L.; Tokorcheck, Justin W.; Monia, Brett P.; Bhanot, Sanjay; Yu, Xing Xian
- Abstract
Studies indicate that the c-Jun N-terminal kinase 1 (JNK1) may act as key mediator of obesity and insulin resistance. JNK1 knockout mice show lower body weight (BW) gain and increased insulin sensitivity when fed a high-fat (HF) diet as compared to wild-type controls. We recently found that antisense reduction of JNK1 expression reduced adiposity and improved metabolic syndrome in ob/ob mice. To further investigate the role of JNK1 in metabolism, we employed antisense technology again to reduce its expression in diet-induced obese mice. Male, 6-week-old C57BL/J6 mice were fed a 58% HF diet for 11 weeks and then treated with a JNK1 specific antisense oligunucleotide (ASO) or a control ASO at 25 mg/kg BW twice a week for 6.5 weeks. JNK1 ASO reduced JNK1 mRNA by ∼ 80% in liver, ∼ 65% in white adipose tissue (WAT), and ∼ 70% in brown adipose tissue. As compared to controls, JNK1 ASO treatment did not change food intake. However, treatment decreased BW (34.0 ± 1.1 vs. 38.0 ± 1.8 g in controls), epididymal fat pad weight (0.77 ± 0.15 vs. 1.29 ± 0.17 g in controls) and whole body fat content (7.2 ± 0.9 vs. 10.4 ± 1.0 g in controls), and increased metabolic rate. Furthermore, treatment lowered both fed and fasting plasma glucose and insulin levels, improved glucose and insulin tolerance, and reduced plasma cholesterol (C) levels (total C by ∼ 35%, HDL-C by ∼ 42% and LDL-C by ∼ 43%). These positive observations are consistent with the data on the changes in gene expression in this group which showed: 1) increased UCP2 mRNA levels in liver, WAT and muscle by 70-260%; 2) reduced mRNA levels of ACC1 and SCD1 in both liver and WAT by 30-40%; and 3) reduced G6Pase mRNA levels by 70% and increased glycogen synthase mRNA levels by 60% in liver. These data extend our previous findings in ob/ob mice, and further indicate that specific reduction of JNK1 expression in peripheral tissues results in increased fuel combustion and decreased lipogenesis in this model. Thus, JNK1 appears to play an important role in whole body metabolism and therapeutic inhibition of JNK1 in major metabolic tissues could provide clinical benefit for obesity and metabolic syndrome.
- Subjects
GENE expression; OBESITY; INSULIN resistance; METABOLIC syndrome; ADIPOSE tissues; BLOOD sugar; LABORATORY mice
- Publication
Diabetes, 2007, Vol 56, pA456
- ISSN
0012-1797
- Publication type
Article