MEDIATORS AND MODIFIERS OF NF-kappaB IN INSULIN RESISTANCE

Summary

Principal Investigator: Steven E Shoelson
Abstract: 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.
Funding Period: ----------------2010 - ---------------2010-
more information: NIH RePORT

Top Publications

  1. ncbi Tag polymorphisms at the A20 (TNFAIP3) locus are associated with lower gene expression and increased risk of coronary artery disease in type 2 diabetes
    Watip Boonyasrisawat
    Section on Genetics and Epidemiology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA
    Diabetes 56:499-505. 2007
  2. ncbi Obesity, inflammation, and insulin resistance
    Steven E Shoelson
    Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
    Gastroenterology 132:2169-80. 2007
  3. pmc Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes
    Allison B Goldfine
    Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
    Clin Transl Sci 1:36-43. 2008
  4. pmc Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters
    Markus Feuerer
    Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Joslin Diabetes Center, Boston, Massachusetts, USA
    Nat Med 15:930-9. 2009
  5. pmc Inflammation and adipose tissue macrophages in lipodystrophic mice
    Laura Herrero
    Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 107:240-5. 2010
  6. pmc Sustained NF-κB activation and inhibition in β-cells have minimal effects on function and islet transplant outcomes
    Aileen J F King
    Diabetes Research Group, King s College London, London, United Kingdom Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States of America
    PLoS ONE 8:e77452. 2013
  7. ncbi Muscle-specific inhibition of the classical nuclear factor-κB pathway is protective against diaphragmatic weakness in murine endotoxemia
    Tatsuma Okazaki
    1Meakins Christie Laboratories and Respiratory Division, McGill University, Montreal, QC, Canada 2Royal Military College Saint Jean, Saint Jean sur Richelieu, QC, Canada 3Joslin Diabetes Center and Harvard Medical School, Boston, MA
    Crit Care Med 42:e501-9. 2014
  8. pmc Insulin receptor activation with transmembrane domain ligands
    Jongsoon Lee
    From the Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215
    J Biol Chem 289:19769-77. 2014

Detail Information

Publications8

  1. ncbi Tag polymorphisms at the A20 (TNFAIP3) locus are associated with lower gene expression and increased risk of coronary artery disease in type 2 diabetes
    Watip Boonyasrisawat
    Section on Genetics and Epidemiology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA
    Diabetes 56:499-505. 2007
    ..04 and 0.028, respectively). These findings point to variability in the A20/TNFAIP3 gene as a modulator of CAD risk in type 2 diabetes. This effect is mediated by allelic differences in A20 expression...
  2. ncbi Obesity, inflammation, and insulin resistance
    Steven E Shoelson
    Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
    Gastroenterology 132:2169-80. 2007
    ..We review the rapidly expanding body of animal and clinical data that support potential roles for inflammation in the pathogenesis of insulin resistance and type 2 diabetes mellitus...
  3. pmc Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes
    Allison B Goldfine
    Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
    Clin Transl Sci 1:36-43. 2008
    ..We studied the efficacy of salsalate in reducing glycemia and insulin resistance and potential mechanisms of action to validate NF-kappaB as a potential pharmacologic target in diabetes...
  4. pmc Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters
    Markus Feuerer
    Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Joslin Diabetes Center, Boston, Massachusetts, USA
    Nat Med 15:930-9. 2009
    ..These observations suggest that harnessing the anti-inflammatory properties of T(reg) cells to inhibit elements of the metabolic syndrome may have therapeutic potential...
  5. pmc Inflammation and adipose tissue macrophages in lipodystrophic mice
    Laura Herrero
    Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 107:240-5. 2010
    ..Although ATMs are even more abundant in lipodystrophy than in obesity, they have distinct phenotypes and likely roles in tissue remodeling, but do not appear to be involved in the pathogenesis of insulin resistance...
  6. pmc Sustained NF-κB activation and inhibition in β-cells have minimal effects on function and islet transplant outcomes
    Aileen J F King
    Diabetes Research Group, King s College London, London, United Kingdom Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States of America
    PLoS ONE 8:e77452. 2013
    ....
  7. ncbi Muscle-specific inhibition of the classical nuclear factor-κB pathway is protective against diaphragmatic weakness in murine endotoxemia
    Tatsuma Okazaki
    1Meakins Christie Laboratories and Respiratory Division, McGill University, Montreal, QC, Canada 2Royal Military College Saint Jean, Saint Jean sur Richelieu, QC, Canada 3Joslin Diabetes Center and Harvard Medical School, Boston, MA
    Crit Care Med 42:e501-9. 2014
    ..We investigated the potential protective effect upon the diaphragm of inhibiting nuclear factor-κB only within muscle fibers during acute endotoxemia...
  8. pmc Insulin receptor activation with transmembrane domain ligands
    Jongsoon Lee
    From the Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215
    J Biol Chem 289:19769-77. 2014
    ..IR-TM also activates mutated receptors from patients with severe insulin resistance, which do not respond to insulin. These results show that IR can be activated through a pathway that bypasses its canonical ligand-binding domain. ..