In the past decade, it became clear that obesity is associated with chronic inflammation and this chronic inflammatory response plays an important role in metabolic deterioration. We have previously identified the role of c-Jun N-terminal kinase, JNK, as a key player integrating inflammatory and metabolic pathways in obesity as well as causing insulin resistance and type 2 diabetes. We also identified endoplasmic reticulum stress as a potential mechanism contributing to the activation of this pathway and causing insulin resistance and type 2 diabetes. Our recent studies exploring the mechanisms linking organelle function to activation of inflammatory and stress signaling cascades and insulin action, led us to a well-established pathogen sensing pathway mediated by the double-stranded RNA dependent protein kinase, PKR. We made exiting observations showing the marked activation of this kinase, which can act upstream of JNK and the eukaryotic initiation factor alpha (eIF2a) kinase, in obesity and insulin resistance. Our preliminary studies support that PKR is a required component of JNK activation in obesity and its absence results in marked protection against insulin resistance and type 2 diabetes. In this proposal, we will study the regulation and function of this kinase in obesity, insulin resistance, and type 2 diabetes, identify the cellular and molecular targets, characterize its role in linking the critical stress signaling pathways with insulin action, explore therapeutic potential through chemical intervention, and study mechanisms of action. A key question in the field is related to coordinated action of several inflammatory kinases during obesity and metabolic stress leading to insulin resistance and obesity. If our postulate is valid, PKR may provide a very critical mechanistic insight as an integrating molecule between inflammatory pathways and metabolic stimuli. For example, we observed that PKR is stimulated by lipids and critical for JNK activation and directly interacts and phosphorylates an important substrate of the insulin receptor, IRS-1. Others have suggested that PKR also interacts with IKK and eIF2a is a well-characterized substrate connecting PKR to ER function. We plan to pursue the protein complexes assembled around PKR at baseline and stress conditions, including lipid exposure, using proteomics approaches and investigate the molecular basis of these intermolecular interactions. Taken together with our observation supporting this application and published reports, we believe there will be opportunities to study the assembly of the key molecules in chronic inflammation and metabolic disease. Our long-term vision is to identify the components and characterize the function of a """"""""stress complex"""""""" (or a metabolic inflammasome), which is potentially central to metabolic inflammation by integrating the key components of inflammatory signaling pathways and insulin action.

Public Health Relevance

Chronic metabolic disease, such as obesity, insulin resistance, and diabetes are among the most common diseases with adverse effects on quality of life worldwide. Despite their enormous burden on human life, the preventive and therapeutic opportunities are limited and there is ongoing need for new and more effective remedies. Our project aims to identify core mechanisms that give rise to these pathologies. Our focus is on the role of chronic inflammation in metabolic disease, with a focus on insulin resistance and diabetes. We postulate that we have discovered a novel mechanism that might explain the coordinate action of many inflammatory signaling pathways and how these mechanisms are integrated to disrupt metabolism. Most importantly, the mechanism that we plan to study is a reversible mechanism and hence could be the basis of future therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052539-15
Application #
8281671
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Haft, Carol R
Project Start
1998-03-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
15
Fiscal Year
2012
Total Cost
$423,808
Indirect Cost
$164,598
Name
Harvard University
Department
Genetics
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Babaev, Vladimir R; Yeung, Michele; Erbay, Ebru et al. (2016) Jnk1 Deficiency in Hematopoietic Cells Suppresses Macrophage Apoptosis and Increases Atherosclerosis in Low-Density Lipoprotein Receptor Null Mice. Arterioscler Thromb Vasc Biol 36:1122-31
Yilmaz, Mustafa; Claiborn, Kathryn C; Hotamisligil, Gökhan S (2016) De Novo Lipogenesis Products and Endogenous Lipokines. Diabetes 65:1800-7
Yang, Ling; Licastro, Danilo; Cava, Edda et al. (2016) Long-Term Calorie Restriction Enhances Cellular Quality-Control Processes in Human Skeletal Muscle. Cell Rep 14:422-8
Nakamura, Takahisa; Kunz, Ryan C; Zhang, Cai et al. (2015) A critical role for PKR complexes with TRBP in Immunometabolic regulation and eIF2α phosphorylation in obesity. Cell Rep 11:295-307
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; Arduini, Alessandro; Baccaro, Brenna et al. (2014) Small-molecule inhibitors of PKR improve glucose homeostasis in obese diabetic mice. Diabetes 63:526-34
Arruda, Ana Paula; Pers, Benedicte M; Parlakgül, Güneş et al. (2014) Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity. Nat Med 20:1427-35
Cao, Haiming; Sekiya, Motohiro; Ertunc, Meric Erikci et al. (2013) Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. Cell Metab 17:768-78

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