This application aims to identify initiating molecular and cellular events leading to the induction of obesity- and diet-induced insulin resistance. Our previous studies identified inflammation, specifically mediated by IKK? and NF-?B, as an underlying feature of insulin resistance. We have found that (A) NF-?B is activated by obesity and Western diet in fat and liver, but not muscle, (B) this leads to the production of proinflammatory cytokines (e.g. IL-6, resistin, ? IL-1?, TNF-a) and other markers and potential mediators of inflammation associated with the metabolic syndrome (e.g. CRP, PAI-1, etc.), (C) transgenic activation of NF-?B in fat or liver mimics these events and causes systemic insulin resistance in the absence of obesity, (D) insulin resistance is transmissible by transplanting affected fat, (E) insulin resistance is reversible by neutralizing cytokines stimulated by NF-?B in fat or liver, and (F), perhaps most importantly, inhibition of IKK? and NF-?B, either genetically or pharmacologically, reverses insulin resistance in animals and humans. To identify how Western diet and obesity incite this subacute inflammatory cascade, we have examined the known activators of ? NF-?B, including reactive oxygen (ROS), ER stress, PKC enzymes or proinflammatory cytokines. While any or all of these may activate NF-?B and cause insulin resistance under certain conditions, our attention has been drawn to the toll receptors (TLRs). The 13 members of the TLR family (including ? IL-1R and IL-18R) mediate their effects on NF-?B through common signaling pathways. MyD88, IRAK4 and IRAK-M in particular provide an opportunity to investigate this large field by manipulating only three key proteins. Preliminary results with MyD88-/-, MyD88+/- and IRAK4+/- mice show that decreases in TLR signaling reverse diet-induced insulin resistance. Proposed experiments use these and other genetic models to determine the tissue specific roles of TLR signaling in insulin resistance. 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
Research Project (R01)
Project #
5R01DK073547-02
Application #
7179301
Study Section
Special Emphasis Panel (ZRG1-EMNR-B (90))
Program Officer
Blondel, Olivier
Project Start
2006-02-15
Project End
2011-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
2
Fiscal Year
2007
Total Cost
$298,194
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
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
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
Goldfine, Allison B; Fonseca, Vivian; Shoelson, Steven E (2011) Therapeutic approaches to target inflammation in type 2 diabetes. Clin Chem 57:162-7
Mathis, Diane; Shoelson, Steven E (2011) Immunometabolism: an emerging frontier. Nat Rev Immunol 11:81

Showing the most recent 10 out of 14 publications