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Updated: Jul 4, 2026
An Adipocyte Cell Culture Model to Study the Impact of Protein and Micro-RNA Modulation on Adipocyte Function
Published on: May 4, 2021
Reduction of JNK1 expression with antisense oligonucleotide improves adiposity in obese mice
Xing Xian Yu1, Susan F Murray, Lynnetta Watts
1Department of Antisense Drug Discovery, Isis Pharmaceuticals, 1896 Rutherford Rd., Carlsbad, CA 92008, USA. xyu@isisph.com
Abstract:
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-beta(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 PKCepsilon by 40-70% and increased levels of UCP2 and PPARalpha 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.
Insights
Inhibition of c-Jun N-terminal kinase 1 (JNK1) using antisense oligonucleotide (ASO) treatment reduced body weight and fat content in obese mice. This metabolic improvement was linked to increased fuel combustion and reduced fat synthesis.
Area of Science:
- Metabolic research
- Obesity studies
- Molecular biology
Background:
- Obesity is a complex metabolic disorder associated with numerous health complications.
- JNK1 (c-Jun N-terminal kinase 1) plays a role in cellular stress responses and metabolic regulation.
- Understanding JNK1's role is crucial for developing effective obesity treatments.
Purpose of the Study:
- To investigate the metabolic effects of inhibiting JNK1 in mouse models of obesity.
- To determine if JNK1 inhibition can ameliorate key features of metabolic dysfunction.
Main Methods:
- Utilized JNK1-specific antisense oligonucleotide (ASO) treatment in ob/ob and diet-induced obese mice.
- Administered JNK1 ASO or control ASO twice weekly for 6-7 weeks.
- Quantified JNK1 mRNA and activity, body weight, fat content, metabolic rate, plasma lipids, and gene expression in liver, fat, and brown adipose tissue (BAT).
- Assessed insulin signaling pathways and hepatocyte lipogenesis and fatty acid oxidation rates.
Main Results:
- JNK1 ASO significantly reduced JNK1 expression and activity in liver and fat.
- Treatment lowered body weight, fat pad weight, and whole-body fat content without altering food intake.
- Metabolic rate increased, accompanied by reduced plasma cholesterol, improved liver steatosis, and enhanced insulin sensitivity.
- Observed significant changes in gene expression related to fatty acid metabolism and energy expenditure in adipose tissue, liver, and BAT.
- JNK1 inhibition improved insulin signaling (pAkt) and reduced markers of insulin resistance (pIRS-1) in liver and fat.
- Hepatocyte studies showed decreased de novo lipogenesis and increased fatty acid oxidation.
Conclusions:
- Inhibition of JNK1 expression in peripheral tissues improves adiposity and metabolic parameters in obese mice.
- JNK1 inhibition enhances fuel combustion and reduces lipogenesis, suggesting a therapeutic potential for obesity and related metabolic disorders.
- Targeting JNK1 offers a promising strategy for managing obesity and associated metabolic abnormalities.
