The previous cycle of this grant hypothesized a critical role for the inflammatory IKKbeta/NF-kappaB pathway in the pathogenesis of obesity- and diet-induced insulin resistance. We now know that the pathway is activated in fat and liver by obesity and high fat diet (HFD) and that activation of NF-kappaB in fat and liver causes insulin resistance, at least in part due to the production of proinflammatory cytokines (IL-6, resistin, IL-1beta, TNF-alpha). Inhibition of IKKbeta and NF-kappaB, either genetically or pharmacologically, and cytokine neutralization reverse insulin resistance in animals and/or humans. Elevations in inflammatory markers that are seen in patients are readily reproduced in rodent models dietary and genetically induced insulin resistance. These are reversed in both rodents and humans in parallel with improvements in insulin resistance and dramatic reductions in triglyceride, free fatty acid and glucose levels. To continue developing and testing these hypotheses, we now propose a comprehensive plan to identify intracellular proteins that modulate NF-kappaB signaling and insulin resistance. In addition to the cytokines listed above, other NF-kappaB targets induced by HFD and obesity in fat and liver are associated with the metabolic syndrome and atherosclerosis (CRP, PAI-1, SAA-1, VCAM1, ICAM1, iNOS and COX2). As the subject of this proposal we also see constitutive, NF-kappaB dependent expression of A20, IKKi/epsilon, and IkappaBzeta, in fat and liver of obese/HFD rodent models. These normally inducible regulators and/or mediators of NF-kappaB signaling have intriguing functions in host defense. We plan to determine if they also function in insulin resistance. A20 induction limits NF-kappaB signaling by altering the ubiquitination of upstream signaling proteins;NF-kappaB induces the expression of IKKi/epsilon, a Ser/Thr kinase that inhibits insulin signaling;and IkappaBzeta, unlike IkappaBalpha, selectively increases expression of a few interesting NF-kappaB targets such as IL-6. Experiments presented in this application determine the in vivo roles of these proteins in fat and liver, delving further into the mechanisms of HFD/obesity-induced insulin resistance by looking both at tissue-specific effects and inter-organ cross-talk. The findings will improve our understanding of the role of subacute 'inflammation'in insulin resistance, T2D and the metabolic syndrome, and may identify new and more selective targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
3R37DK051729-14S2
Application #
8108568
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Abraham, Kristin M
Project Start
1996-09-21
Project End
2011-06-30
Budget Start
2010-07-20
Budget End
2011-06-30
Support Year
14
Fiscal Year
2010
Total Cost
$459,537
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Goldfine, Allison B; Shoelson, Steven E (2017) Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk. J Clin Invest 127:83-93
Okazaki, Tatsuma; Liang, Feng; Li, Tong et al. (2014) Muscle-specific inhibition of the classical nuclear factor-?B pathway is protective against diaphragmatic weakness in murine endotoxemia. Crit Care Med 42:e501-9
Lee, Jongsoon; Miyazaki, Masaya; Romeo, Giulio R et al. (2014) Insulin receptor activation with transmembrane domain ligands. J Biol Chem 289:19769-77
Romeo, Giulio R; Pae, Munkyong; Eberlé, Delphine et al. (2013) Profilin-1 haploinsufficiency protects against obesity-associated glucose intolerance and preserves adipose tissue immune homeostasis. Diabetes 62:3718-26
Goldfine, A B; Conlin, P R; Halperin, F et al. (2013) A randomised trial of salsalate for insulin resistance and cardiovascular risk factors in persons with abnormal glucose tolerance. Diabetologia 56:714-23
Kim, Myung-Sunny; Yamamoto, Yasuhiko; Kim, Kyungjin et al. (2013) Regulation of diet-induced adipose tissue and systemic inflammation by salicylates and pioglitazone. PLoS One 8:e82847
King, Aileen J F; Guo, Yongjing; Cai, Dongsheng et al. (2013) Sustained NF-?B activation and inhibition in ?-cells have minimal effects on function and islet transplant outcomes. PLoS One 8:e77452
Wong, Man C; van Diepen, Janna A; Hu, Lihui et al. (2012) Hepatocyte-specific IKK? expression aggravates atherosclerosis development in APOE*3-Leiden mice. Atherosclerosis 220:362-8
Schakman, O; Dehoux, M; Bouchuari, S et al. (2012) Role of IGF-I and the TNF?/NF-?B pathway in the induction of muscle atrogenes by acute inflammation. Am J Physiol Endocrinol Metab 303:E729-39
Langen, Ramon C J; Haegens, Astrid; Vernooy, Juanita H J et al. (2012) NF-?B activation is required for the transition of pulmonary inflammation to muscle atrophy. Am J Respir Cell Mol Biol 47:288-97

Showing the most recent 10 out of 26 publications