The role of non-canonical IKKs in metabolic disease We hypothesize that hepatic IKK-epsilon and TBK1 are important metabolic mediators affecting hepatic steatosis and systemic metabolic disease. In a high throughput screen for inhibitors of IKK? kinase activity, we identified the FDA approved drug, amlexanox, which we confirmed to be an IKK?/TBK1 specific inhibitor. Consistent with our hypothesis, administration of amlexanox to obese mice produces reversible weight loss, insulin sensitivity and attenuation of hepatic steatosis, without affecting food intake. Since the activities of IKK-epsilon and TBK1 are elevated in both liver and fat in response to obesity, and since it is well known that the metaboli activities of these tissues can impact each other, the tissue and cell autonomous nature of these effects remains uncertain. I will attempt to evaluate whether the impact of IKK-epsilon/TBK1 blockade on hepatic metabolism is direct or indirect. Using amlexanox as a tool to acutely inhibit IKK-epsilon/TBK1 in the context of obesity when their activity is high, I hope to identify the primary signaling pathways downstream of IKK-epsilon and TBK1. We have previously published on the role of IKK-epsilon in metabolic disease. Here I propose to specifically investigate the role of TBK1, the other non-canonical IKK, in the development and persistence of metabolic disease, using Amlexanox treatment in IKK-epsilon knockout mice, as well as liver specific TBK1 knockdown and overexpression. Finally the liver specific role of IKK- epsilon will also be investigated using hepatic-specific IKK-epsilon overexpression. The results of these experiments will illuminate the role of hepatic IKK-epsilon and TBK1 in liver metabolism as well as systemic metabolic regulation. This research will contribute to the basic understanding of metabolic diseases and hopefully lead to new therapeutic approaches to treat or prevent these devastating disorders.

Public Health Relevance

World-wide obesity rates are increasing rapidly, posing a significant threat to public health. Here we propose to investigate the role of non-canonical IKKs in the development of obesity-associated metabolic diseases. This research will contribute to the basic understanding of metabolic diseases and hopefully lead to new therapeutic approaches to treat or prevent these devastating disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK096851-02
Application #
8542491
Study Section
Special Emphasis Panel (ZDK1-GRB-R (O1))
Program Officer
Castle, Arthur
Project Start
2012-09-01
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$52,190
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109