There is little doubt that we are in the midst of a worldwide epidemic of diabetes. Insulin resistance is recognized as a characteristic trait of the disease, defined by the inability to respond to normal circulating levels of insulin, and is usuall closely associated with obesity. Recent data suggest an inflammatory link between obesity and insulin resistance. However, the teleological reasons or these findings, and the manner in which energy storage is preserved in the absence of insulin action remain a mystery. We hypothesize that the induction of a counter-inflammatory program plays a key role in preserving energy storage, reducing energy expenditure and ensuring that insulin resistance is maintained during obesity. We will explore this hypothesis with three aims: 1) we will elucidate the temporal and spatial aspect of counter-inflammation, paying particular attention to the induction of the kinases IKK? and TBK1. We will knock these out in tissue-specific manner to determine the primary sites at which these events occur relevant to changes in metabolism;2) we will deeply explore the molecular targets of these kinases, focusing on their ability to repress sympathetic activation of adipocytes though changes in cAMP levels, and 3) we will evaluate the role of these counterinflammatory kinases in the generation and sustaining of insulin resistance by examining insulin receptor pathways in cells.

Public Health Relevance

The molecular mechanisms linking obesity and type 2 diabetes remain an enigma. We will investigate the role of inflammation as a link between these states. We will study the roles of the protein kinases IKKe and TBK1 in this process, trying to understand how these enzymes function in mice to support continued energy storage in the face of insulin resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060591-12
Application #
8737881
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Abraham, Kristin M
Project Start
2002-02-01
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Cho, Chun-Seok; Park, Hwan-Woo; Ho, Allison et al. (2017) Lipotoxicity induces hepatic protein inclusions through TBK1-mediated p62/SQSTM1 phosphorylation. Hepatology :
Oral, Elif A; Reilly, Shannon M; Gomez, Andrew V et al. (2017) Inhibition of IKK? and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes. Cell Metab 26:157-170.e7
Bridges, Dave; Saltiel, Alan R (2015) Phosphoinositides: Key modulators of energy metabolism. Biochim Biophys Acta 1851:857-66
Fang, Sungsoon; Suh, Jae Myoung; Reilly, Shannon M et al. (2015) Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 21:159-65
Reilly, Shannon M; Ahmadian, Maryam; Zamarron, Brian F et al. (2015) A subcutaneous adipose tissue-liver signalling axis controls hepatic gluconeogenesis. Nat Commun 6:6047
Hochberg, Irit; Harvey, Innocence; Tran, Quynh T et al. (2015) Gene expression changes in subcutaneous adipose tissue due to Cushing's disease. J Mol Endocrinol 55:81-94
Reilly, Shannon M; Saltiel, Alan R (2014) Countering inflammatory signals in obesity. Nat Immunol 15:410-1
Wang, Guo-Xiao; Cho, Kae Won; Uhm, Maeran et al. (2014) Otopetrin 1 protects mice from obesity-associated metabolic dysfunction through attenuating adipose tissue inflammation. Diabetes 63:1340-52
Lu, Binbin; Bridges, Dave; Yang, Yemen et al. (2014) Metabolic crosstalk: molecular links between glycogen and lipid metabolism in obesity. Diabetes 63:2935-48
Reilly, Shannon M; Saltiel, Alan R (2014) Obesity: A complex role for adipose tissue macrophages. Nat Rev Endocrinol 10:193-4

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