Understanding glucose production in the liver

A study led by Kanazawa University scientists has revealed key steps in the biomolecular processes that increase glucose production in the livers of obese and diabetic patients.

Hiroshi Inoue and co-workers from around Japan and Singapore explained how obesity-induced stress in the endoplasmic reticulum (ER) – an organelle within cells that is essential for synthesis of proteins and lipids – produces excess glucose in the liver. Specifically, ER stress inhibits the activity of a transcription factor called signal transducer and activator of transcription 3 (STAT3).

In previous work, the team showed that insulin action in the brain induces STAT3 activation in the liver, where STAT3 plays a role in suppressing the genetic expression of glucose-producing (gluconeogenic) enzymes. However it was not clear whether ER stress and the resultant glucose production was related to any change in STAT3 activity.

For their latest experiments, the researchers collected genetically obese, diabetic mice and analyzed their liver cells. They found that ER stress suppresses Janus kinase (JAK), an enzyme that is usually essential for activating STAT3 via phosphorylation.

The ER stress also enhances an enzyme called histone deacetylase (HDAC). HDAC is known to cause deacetylation of STAT3, which reduces STAT3 activity.

The two processes of dephosphorylation and deacetylation act together to suppress STAT3, thereby allowing gluconeogenic enzymes to go into over-drive producing glucose. By uncovering such details of the complex biomolecular processes in livers, Inoue and co-workers are increasing our overall understanding of obesity and diabetes, which should allow more effective drugs to be developed.

Publication and Affiliation
Kumi Kimura1, Tomoko Yamada1,2, Michihiro Matsumoto3, Yoshiaki Kido4,5, Tetsuya Hosooka4, Shun-ichiro Asahara4, Tomokazu Matsuda4, Tsuguhito Ota1, Hiroshi Watanabe6, Yoshimichi Sai2, Kenichi Miyamoto2, Shuichi Kaneko7, Masato Kasuga3, & Hiroshi Inoue1*. Endoplasmic reticulum stress inhibits STAT3-dependent suppression of hepatic gluconeogenesis via dephosphorylation and deacetylation. Diabetes 61, 61-73 (2012). Link

1. Frontier Science Organization, Kanazawa University, Kanazawa, Ishikawa, Japan
2. Department of Medicinal Informatics, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
3. Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
4. Department of Internal Medicine, Division of Diabetes, Metabolism, and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
5. Department of Biophysics, Division of Medical Chemistry, Kobe University Graduate School of Health Sciences, Kobe, Japan
6. Brand’s Brain Research Centre, Cerebos Pacific Limited, Singapore
7. Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan

*corresponding author, e-mail address: inoue-h@staff.kanazawa-u.ac.jp

ID: 201212A013