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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Abraham, Kristin M
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Skorobogatko, Yuliya; Dragan, Morgan; Cordon, Claudia et al. (2018) RalA controls glucose homeostasis by regulating glucose uptake in brown fat. Proc Natl Acad Sci U S A 115:7819-7824
Zhao, Peng; Wong, Kai In; Sun, Xiaoli et al. (2018) TBK1 at the Crossroads of Inflammation and Energy Homeostasis in Adipose Tissue. Cell 172:731-743.e12
Cho, Chun-Seok; Park, Hwan-Woo; Ho, Allison et al. (2018) Lipotoxicity induces hepatic protein inclusions through TANK binding kinase 1-mediated p62/sequestosome 1 phosphorylation. Hepatology 68:1331-1346
Ahmadian, Maryam; Liu, Sihao; Reilly, Shannon M et al. (2018) ERR? Preserves Brown Fat Innate Thermogenic Activity. Cell Rep 22:2849-2859
Beyett, Tyler S; Gan, Xinmin; Reilly, Shannon M et al. (2018) Design, synthesis, and biological activity of substituted 2-amino-5-oxo-5H-chromeno[2,3-b]pyridine-3-carboxylic acid derivatives as inhibitors of the inflammatory kinases TBK1 and IKK? for the treatment of obesity. Bioorg Med Chem 26:5443-5461
Beyett, Tyler S; Gan, Xinmin; Reilly, Shannon M et al. (2018) Carboxylic Acid Derivatives of Amlexanox Display Enhanced Potency toward TBK1 and IKK? and Reveal Mechanisms for Selective Inhibition. Mol Pharmacol 94:1210-1219
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
Baeza-Raja, Bernat; Sachs, Benjamin D; Li, Pingping et al. (2016) p75 Neurotrophin Receptor Regulates Energy Balance in Obesity. Cell Rep 14:255-68
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
Bridges, Dave; Saltiel, Alan R (2015) Phosphoinositides: Key modulators of energy metabolism. Biochim Biophys Acta 1851:857-66

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