Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.
We show that NF-kappaB and transcriptional targets are activated in liver by obesity and high-fat diet (HFD). We have matched this state of chronic, subacute 'inflammation' by low-level activation of NF-kappaB in the liver of transgenic mice, designated LIKK, by selectively expressing constitutively active IKK-b in hepatocytes. These mice exhibit a type 2 diabetes phenotype, characterized by hyperglycemia, profound hepatic insulin resistance, and moderate systemic insulin resistance, including effects in muscle. The hepatic production of proinflammatory cytokines, including IL-6, IL-1beta and TNF-alpha, was increased in LIKK mice to a similar extent as induced by HFD in in wild-type mice. Parallel increases were observed in cytokine signaling in liver and mucscle of LIKK mice. Insulin resistance was improved by systemic neutralization of IL-6 or salicylate inhibition of IKK-beta. Hepatic expression of the IkappaBalpha superrepressor (LISR) reversed the phenotype of both LIKK mice and wild-type mice fed an HFD. These findings indicate that lipid accumulation in the liver leads to subacute hepatic 'inflammation' through NF-kappaB activation and downstream cytokine production. This causes insulin resistance both locally in liver and systemically.
Cai
Dongsheng
D
Joslin Diabetes Center & Department of Medicine, Harvard Medical School, One Joslin Place, Boston, Massachusetts 02215, USA.
Yuan
Minsheng
M
Frantz
Daniel F
DF
Melendez
Peter A
PA
Hansen
Lone
L
Lee
Jongsoon
J
Shoelson
Steven E
SE
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism; D050260:Carbohydrate Metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000473:pathology / Q000502:physiology*; D006801:Humans; D051550:I-kappa B Kinase; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D012459:Salicylates / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D004041:Dietary Fats; D007328:Insulin; D015850:Interleukin-6; D016328:NF-kappa B; D012459:Salicylates; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse