The role of non-canonical IKKs in metabolic disease

Summary

Principal Investigator: SHANNON MARIE REILLY
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2012-09-01 - 2015-08-31
more information: NIH RePORT

Top Publications

  1. pmc An inhibitor of the protein kinases TBK1 and IKK-ɛ improves obesity-related metabolic dysfunctions in mice
    Shannon M Reilly
    Life Sciences Institute, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
    Nat Med 19:313-21. 2013

Detail Information

Publications1

  1. pmc An inhibitor of the protein kinases TBK1 and IKK-ɛ improves obesity-related metabolic dysfunctions in mice
    Shannon M Reilly
    Life Sciences Institute, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
    Nat Med 19:313-21. 2013
    ..Because of its record of safety in patients, amlexanox may be an interesting candidate for clinical evaluation in the treatment of obesity and related disorders...

Research Grants30

  1. Nicotinamide N-methyltransferase (NNMT) in obesity and insulin resistance
    Qin Yang; Fiscal Year: 2013
    ..The project will determine the critical role of NNMT in the development of obesity and type 2 diabetes. Potentially NNMT could be a new therapeutic target to prevent and treat obesity and type 2 diabetes. ..
  2. Novel Methods to Assess the Effects of Chemicals on Child Development
    Susan L Schantz; Fiscal Year: 2013
    ..This Center's research will fill an important gap in our knowledge by investigating the effects of these chemicals, both alone and combination with a high fat diet on reproductive and neural development. ..
  3. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
    ..abstract_text> ..
  4. Mechanisms and metabolic implications of LRP130 in NAFLD
    Marcus P Cooper; Fiscal Year: 2013
    ..This proposal will investigate the role of a gene called LRP130 in fatty liver disease, and may provide new ways to treat diabetes and heart disease. ..
  5. MiR-33 and Aging: Implications for Metabolic Syndrome
    Leigh Goedeke; Fiscal Year: 2013
    ....
  6. MMC and VICC: Partnership for Survivorship (1 of 2)
    Maureen Sanderson; Fiscal Year: 2013
    ..abstract_text> ..
  7. Obesity increased cancer risk by NKT cell depletion (PQ1)
    Mark A Exley; Fiscal Year: 2013
    ..We will determine whether NKT dysfunction is exacerbated in obese cancer and their therapeutic potential. ..
  8. NUTRITION OBESITY RESEARCH CENTER
    Michael W Schwartz; Fiscal Year: 2013
    ..However, over the past several years, Als have tended to focus their research in the following major areas: 1. Body Weight Regulation and Obesity 2. Adipose Tissue Biology and Inflammation 3. Lipids and Atherosclerosis 4. Diabetes ..
  9. Role of Dab2 in Fatty Liver Disease
    Norbert Leitinger; Fiscal Year: 2013
    ..Specific Aim 2 will determine the mechanistic basis for Dab2-dependent regulation of inflammation and Specific Aim 3 will examine the hypothesis that Dab2 in myeloid cells is essential for cross talk with NK cells in the liver. ..
  10. A Novel Cellular Mechanism for Reducing Hyperlipidemia
    Jingwen Liu; Fiscal Year: 2013
    ....
  11. Cellular Mechanisms for Increased Gluconeogenesis in Type 2 Diabetes
    Varman T Samuel; Fiscal Year: 2013
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  12. Hypo-Lipidemic Actions of Creosote Bush-Derived NDGA
    Salman Azhar; Fiscal Year: 2013
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  13. Hepatic Lipid Mobilization by Nuclear Hormone Receptors
    Yoon Kwang Lee; Fiscal Year: 2013
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  14. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  15. The anti-inflammatory mRNA-binding protein ZFP36 in Obesity and Metabolism
    CALEB BENJAMIN KALLEN; Fiscal Year: 2013
    ..Our work may identify ZFP36 as a new therapeutic target for important medical conditions exacerbated by obesity and inflammation including atherosclerosis and diabetes. ..
  16. Regulation of Bile Acid Synthesis by Nuclear Receptors
    John Y L Chiang; Fiscal Year: 2013
    ..The long-term objectives of this research are to elucidate the molecular mechanism of regulation of CYP7A1 and bile acid metabolism, and pathogenesis and treatment of metabolic diseases such as fatty liver disease, diabetes and obesity. ..
  17. Role of stearoyl CoA desaturase-1 in TLR5 KO mice colitis and metabolic syndrome
    Matam Vijay Kumar; Fiscal Year: 2013
    ..Overall, our research proposal may help in designing oleate-rich dietary formulations and also clarify whether SCD-1 can be targeted to prevent colitis and metabolic diseases ! ..
  18. Role of SIRT3 in Modulation of Lipotoxicity in Liver
    SEAN ALEC NEWSOM; Fiscal Year: 2013
    ..The long-term goal of this project is to dissect the mechanisms surrounding how excess nutrients lead to hyperacetylation of key proteins and to identify a regulatory role for SIRT3 in NAFLD and susceptibility to type 2 diabetes. ..
  19. Role of Perilipin in Hepatic Steatosis and Metabolism
    Thomas A Bowman; Fiscal Year: 2013
    ..These studies will guide the design of new therapeutic targets to prevent insulin resistance and treat type 2 diabetes. ..
  20. Effects of sleep deprivation and high fat diet on human CYP7A1 circadian rhythm
    JESSICA MARIE FERRELL; Fiscal Year: 2013
    ..The proposed studies aim to understand the contribution of deregulated circadian liver metabolism in the progression of diabetes and obesity. ..
  21. Pathobiology of the Enteric System
    Joseph H Szurszewski; Fiscal Year: 2013
    ..This highly-integrated Program will make significant progress toward understanding the pathobiology of the enteric system in gastric emptying disorders and translate this knowledge into new diagnostic tools and therapy. ..