cJun NH2-terminal kinase 1 (JNK1): roles in metabolic regulation of insulin resistance - PubMed (original) (raw)

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cJun NH2-terminal kinase 1 (JNK1): roles in metabolic regulation of insulin resistance

Guadalupe Sabio et al. Trends Biochem Sci. 2010 Sep.

Abstract

The cJun NH(2)-terminal kinase isoform JNK1 is implicated in the mechanism of obesity-induced insulin resistance. Feeding a high-fat diet causes activation of the JNK1 signaling pathway, insulin resistance, and obesity in mice. Germ-line ablation of Jnk1 prevents both diet-induced obesity and insulin resistance. Genetic analysis indicates that the effects of JNK1 on insulin resistance can be separated from effects of JNK1 on obesity. Emerging research indicates that JNK1 plays multiple roles in the regulation of insulin resistance, including altered gene expression, hormone/cytokine production, and lipid metabolism. Together, these studies establish JNK1 as a potential pharmacological target for the development of drugs that might be useful for the treatment of insulin resistance, metabolic syndrome, and type 2 diabetes.

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Figures

Figure 1. Role of JNK1 in adipocytes

Feeding a high fat diet (HFD) causes JNK1 activation in adipocytes, leading to insulin resistance in adipocytes and expression of the adipokine IL6. JNK-mediated phosphorylation of IRS1 might contribute to insulin resistance in adipocytes. The increased concentration of IL6 in the blood up-regulates expression of SOCS3, a protein that targets IRS1 for ubiquitin-mediated degradation and hepatic insulin resistance.

Figure 2. Role of JNK1 in muscle

Feeding a high fat diet (HFD) causes JNK1 activation in muscle and insulin resistance. Loss of JNK1 causes decreased expression of lipoprotein lipase (LPL), an enzyme that promotes absorption of triglycerides (e.g. VLDL; very low density lipoprotein). Increased accumulation of fatty acids (FFA) and increased phosphorylation of IRS1 might contribute to JNK1-mediated insulin resistance.

Figure 3. Role of JNK1 in the central nervous system

Feeding a high fat diet (HFD) causes activation of JNK1 in the hypothalamus and pituitary gland. In the hypothalamus, JNK1 suppresses expression of thyrotropin releasing hormone (TRH); in the pituitary gland, JNK1 activity reduces the expression of thyroid stimulating hormone (TSH). Increased thyroid hormones (T3 and T4) in the blood act to suppress expression of TRH and TSH. Together, these changes regulate energy expenditure, physical activity and food intake. The resulting obesity contributes to insulin resistance in peripheral organs.

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cJun NH2-terminal kinase 1 (JNK1): roles in metabolic regulation of insulin resistance - PubMed (original) (raw)