Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official. Federal government websites often end in . gov or . mil VSports app下载. Before sharing sensitive information, make sure you’re on a federal government site. .

Https

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely V体育官网. .

. 2006 Jul 11;103(28):10741-6.
doi: 10.1073/pnas.0603509103. Epub 2006 Jul 3.

Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance

Gürol Tuncman  1 , Jiro Hirosumi, Giovanni Solinas, Lufen Chang, Michael Karin, Gökhan S Hotamisligil
Affiliations

Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance

Gürol Tuncman et al. Proc Natl Acad Sci U S A. .

Abstract

The c-Jun N-terminal kinases (JNKs) are key regulators of inflammation and interfere with insulin action in cultured cells and whole animals. Obesity increases total JNK activity, and JNK1, but not JNK2, deficiency results in reduced adiposity and improved insulin sensitivity. Interestingly, a higher-than-normal level of JNK activation is observed in Jnk2(-/-) mice, particularly in the liver, indicating an interaction between the isoforms that might have masked the metabolic activity of JNK2 in isolated mutant mice. To address the role of the JNK2 isoform in metabolic homeostasis, we intercrossed Jnk1(-/-) and Jnk2(-/-) mice and examined body weight and glucose metabolism in the resulting mutant allele combinations. Among all of the viable genotypes examined, we observed only reduced body weight and increased insulin sensitivity in Jnk1(-/-) and Jnk1(+/-)Jnk2(-/-) mice. These two groups of mice also exhibited reduced total JNK activity and cytokine expression in liver tissue compared with all other genotypes examined VSports手机版. These data indicate that the JNK2 isoform is also involved in metabolic regulation, but its function is not obvious when JNK1 is fully expressed because of regulatory crosstalk between the two isoforms. .

PubMed Disclaimer

Conflict of interest statement

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.
Fig. 1.
Regulation of JNK activity by obesity and its modulation by isolated JNK1 and JNK2 deficiencies. Total JNK activity was determined in liver, white adipose tissue (WAT), and muscle tissues of WT, ob/ob, ob/ob-TNFR−/−(p55−/−p75−/−), Jnk1−/−, and Jnk2−/− mice. ob/ob, genetic model for leptin deficiency. Numbers below the immunoblots represent fold increase in c-Jun N-terminal phosphorylation. 1, activity in lean WT.
Fig. 2.
Fig. 2.
Body-weight regulation and fatty liver in different Jnk genotypes on a high-fat diet. (A and B) Starting at 3 weeks of age, all progeny from the intercrosses between Jnk1+/− and Jnk2+/− were placed on a regular (A) and high-fat (B) diet and were monitored for their body weight. Five genotypes are shown in these graphs. ∗∗, statistical significance P < 0.01. (C) Liver sections prepared from Jnk1+/+Jnk2+/+, Jnk1+/−Jnk2−/−, Jnk1+/+Jnk2−/−, and Jnk1−/−Jnk2+/+ mice on with a high-fat/high-caloric diet for 17 weeks. Sections were photographed at ×100 after staining with hematoxylin/eosin.
Fig. 3.
Fig. 3.
Biochemical analyses of serum in different Jnk genotypes. Serum samples were collected after an overnight fast from mice of the indicated genotypes after 14 weeks on a high-fat diet. Triglyceride (A), cholesterol (B), insulin (C), and glucose (D) levels were measured. ∗, statistical significance P < 0.05.
Fig. 4.
Fig. 4.
Comparison of insulin sensitivity among different Jnk genotypes. Systemic glucose metabolism and insulin sensitivity were studied by i.p. glucose and i.p. insulin tolerance tests performed on mice kept on a regular (A and C) and high-fat diet (B and D) at 16–17 weeks of age. AUC, area under the curve. ∗, statistical significance P < 0.01.
Fig. 5.
Fig. 5.
Total JNK activity and expression of inflammatory cytokines. Total JNK activity was determined in livers of Jnk1+/−Jnk2−/−, Jnk1−/−Jnk2+/+, and Jnk1+/+Jnk2−/− mice kept on a high-fat diet (A) along with their lean and obese WT controls at 17 weeks of age. Total RNA was extracted from the same liver samples, and IL-12 (B), MCP-1 (C), TNF-α (D), IL-6 (E), and MIF (F) mNA levels were quantified relative to that of 18S ribosomal RNA.
Fig. 6.
Fig. 6.
Binding of JNK1 and JNK2 to IRS-1 and its phosphorylation on Ser-307 residue. (A) GST pulldown of lysates (300 μg/ml) from HEK293T cells transiently expressing IRS-1 in the presence or absence of the competitive inhibitor of JNK substrate docking, Tat-JIP (5 μM). (B and C) GST-JNK1 (B) and GST-JNK2 (C) pulldown experiments using different amounts of extracts from IRS-1-expressing HEK293T cells. (D) GST-JNK1 and GST-JNK2 pulldown kinase assays were performed by using 300 μg/ml of protein lysates from IRS-1-expressing HEK293T cells in the presence or absence of the JNK inhibitor SP600125 (2 μM). IRS-1 Ser-307 phosphorylation was detected by immunoblotting with a phosphospecific antibody.
See this image and copyright information in PMC

References

    1. Wellen K. E., Hotamisligil G. S. J. Clin. Invest. 2005;115:1111–1119. - PMC - PubMed
    1. Hotamisligil G. S., Shargill N. S., Spiegelman B. M. Science. 1993;259:87–91. - "VSports最新版本" PubMed
    1. Uysal K. T., Wiesbrock S. M., Marino M. W., Hotamisligil G. S. Nature. 1997;389:610–614. - PubMed
    1. Ventre J., Doebber T., Wu M., Macnaul K., Stevens K., Pasparakis M., Kollias G., Moller D. E. Diabetes. 1997;46:1526–1531. - PubMed (VSports注册入口)
    1. Shulman G. I. J. Clin. Invest. 2000;106:171–176. - PMC (VSports手机版) - PubMed

Publication types

"V体育官网" MeSH terms