Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance
Tuncman, G., Hirosumi, J., Solinas, G. et al. Proc. Nat. Acad. Sci., 103, 10741-10746 (July 11, 2006).
c-Jun N-terminal kinase (JNK) is known to play a key role in various cellular pathways, including inflammatory changes associated with the development of insulin resistance and obesity. But the relative importance of the two isoforms found in liver, adipose tissue, and muscle had not been investigated previously. This study used JNK1- and JNK2-deficient mice to assess the relationship between the isoforms and their importance to metabolic regulation.
The results support previous research showing JNK activity is increased in obese animals. Moreover, deletion of the Jnk1 gene prevented an increase in total JNK activity and body weight in animals fed a high-fat diet. In contrast, deletion of the Jnk2 gene had no effect on these parameters, suggesting that the JNK2 isoform has no detectable role in metabolic regulation.
However, an examination of mice with the genotypes Jnk1(-/-)Jnk2(+/+) and Jnk1(+/-)Jnk2(-/-) indicates otherwise. These animals had lower body weights and no signs of fatty infiltration of their livers after four months on a high-fat diet. They also had better glucose metabolism and insulin sensitivity, as determined by serum levels and tolerance tests, than other genotypes. Total JNK activity was reduced in these animals as well, in response to a high-fat diet. Homozygous Jnk1(-/-) animals had the lowest enzyme activity of all, while the Jnk(+/-)Jnk2(-/-) had an intermediate level. These genotypes were also characterized as having low pro-inflammatory cytokine mRNA levels in livers of animals fed a high-fat diet. This is consistent with findings that show obesity is marked by low-grade inflammation in insulin-sensitive tissues.
Overall, the results point to an interplay between JNK1 and JNK2 isoforms in the regulation of lipid and glucose metabolism. Thus, the study signals a warning to pharmaceutical companies attempting to develop new drug therapies for metabolic disorders and inflammatory diseases, based on inhibition of JNK. To be maximally effective the compound will likely have to block both JNK1 and JNK2 isoforms.
Message posted by: Keith Markey
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