The close integration of immune and metabolic responses associated with obesity lead to the development of metabolic diseases such as insulin resistance, diabetes, and atherosclerosis. However, the endogenous molecules that signal metabolic stress and the mechanisms that sense and relay such signals to metabolic and immune response systems are incompletely understood. The double stranded RNA-activated protein kinase PKR is activated in response to pathogens and nutrients, and work by our laboratory and others suggests that PKR plays an important role in integrating signaling networks that modulate inflammation and the development of insulin resistance. Based on our preliminary data we propose that the study of PKR activation represents an opportunity to identify the metabolic signals and novel mechanisms at play in immunometabolic regulation. Therefore, the objective of this proposal is to characterize the endogenous lipids and RNAs that modulate PKR activity and the formation of the active PRK complex in the setting of metabolic stress, with the goal of translating these findings to a broader understanding of the molecular signals that contribute to the integration of metabolic stresses and inflammation in obesity. We believe that successful completion of this work has the potential to highlight new therapeutic targets and strategies for use in the fight against the epidemic of obesity and related pathologies.
More than 69% of adults in the U.S. suffer from being overweight or obese, conditions associated with increased risk of developing a number of metabolic diseases including diabetes, cardiovascular disease, asthma, and cancer. The research described in this proposal will investigate the molecular mediators that coordinate metabolic and inflammatory signaling in the establishment of insulin resistance, diabetes, and metabolic disease. These studies are highly relevant to the mission of the NIH because a deeper understanding of the molecular pathways that underlie the connection between obesity, diabetes, and metabolic disease may open doors to new therapeutic strategies for conditions that affect a majority of the population.
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|Hotamisligil, Gökhan S (2017) Inflammation, metaflammation and immunometabolic disorders. Nature 542:177-185|
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|Ertunc, Meric Erikci; Hotamisligil, Gökhan S (2016) Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment. J Lipid Res 57:2099-2114|
|Yilmaz, Mustafa; Claiborn, Kathryn C; Hotamisligil, Gökhan S (2016) De Novo Lipogenesis Products and Endogenous Lipokines. Diabetes 65:1800-7|
|Youssef, Osama A; Safran, Sarah A; Nakamura, Takahisa et al. (2015) Potential role for snoRNAs in PKR activation during metabolic stress. Proc Natl Acad Sci U S A 112:5023-8|
|Yang, Ling; Calay, Ediz S; Fan, Jason et al. (2015) METABOLISM. S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction. Science 349:500-6|
|Arruda, Ana Paula; Hotamisligil, Gökhan S (2015) Calcium Homeostasis and Organelle Function in the Pathogenesis of Obesity and Diabetes. Cell Metab 22:381-97|
|Nakamura, Takahisa; Kunz, Ryan C; Zhang, Cai et al. (2015) A critical role for PKR complexes with TRBP in Immunometabolic regulation and eIF2? phosphorylation in obesity. Cell Rep 11:295-307|
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