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.
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.
|Bridges, Dave; Saltiel, Alan R (2015) Phosphoinositides: Key modulators of energy metabolism. Biochim Biophys Acta 1851:857-66|
|Lu, Binbin; Bridges, Dave; Yang, Yemen et al. (2014) Metabolic crosstalk: molecular links between glycogen and lipid metabolism in obesity. Diabetes 63:2935-48|
|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|
|Reilly, Shannon M; Chiang, Shian-Huey; Decker, Stuart J et al. (2013) An inhibitor of the protein kinases TBK1 and IKK-ýý improves obesity-related metabolic dysfunctions in mice. Nat Med 19:313-21|
|Lumeng, Carey N; Saltiel, Alan R (2011) Inflammatory links between obesity and metabolic disease. J Clin Invest 121:2111-7|
|Chiang, Shian-Huey; Bazuine, Merlijn; Lumeng, Carey N et al. (2009) The protein kinase IKKepsilon regulates energy balance in obese mice. Cell 138:961-75|
|Westcott, Daniel J; Delproposto, Jennifer B; Geletka, Lynn M et al. (2009) MGL1 promotes adipose tissue inflammation and insulin resistance by regulating 7/4hi monocytes in obesity. J Exp Med 206:3143-56|
|Lumeng, Carey N; DelProposto, Jennifer B; Westcott, Daniel J et al. (2008) Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 57:3239-46|
|D'Andrea-Merrins, Matthew; Chang, Louise; Lam, Alice D et al. (2007) Munc18c interaction with syntaxin 4 monomers and SNARE complex intermediates in GLUT4 vesicle trafficking. J Biol Chem 282:16553-66|
|Lumeng, Carey N; Deyoung, Stephanie M; Saltiel, Alan R (2007) Macrophages block insulin action in adipocytes by altering expression of signaling and glucose transport proteins. Am J Physiol Endocrinol Metab 292:E166-74|
Showing the most recent 10 out of 26 publications