Cai, D. et al. Local and systemic insulin resistance due to hepatic activation of IKK- and NF-kB. Nat. Med. 11, 183-190

Joslin Diabetes Center & Department of Medicine, Harvard Medical School, One Joslin Place, Boston, Massachusetts 02215, USA.
Nature Medicine (Impact Factor: 27.36). 03/2005; 11(2):183-90. DOI: 10.1038/nm1166
Source: PubMed


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.

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    • "Obesity and diabetes are associated with chronic low-grade inflammatory state through release of pro-inflammatory cytokines including TNF-a, and IL-6 (Hamminga et al., 2006). In rodents, a high-fat diet (HFD) results in NAFLD and up-regulation of NF-kB activity, which leads to hepatic production of various proinflammatory cytokines and activation of Kupffer cells and macrophages (Bhatia et al., 2012; Cia et al., 2005). "
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    • "Most studies have focused on the development of obesity and insulin insensitivity in rodent models of either genetic or diet-induced obesity after several weeks on a HF diet. These studies have shown that insulin insensitivity is related to cellular inflammation involving the JNK1 and IKKβ-NFκB cascade [11], [12], while relatively few studies have focused on the rapid induction of insulin insensitivity seen within 1 week of HF diet. Nonetheless, studies of early responses to a HF diet are emerging with one study showing that insulin insensitivity after 1 week of HF diet in the C57Bl/6 mouse is the consequence of insulin insensitivity in the vascular endothelium [13], and another demonstrating that hypothalamic markers of inflammation are activated between 1 and 3 days on a HF diet [14]. "
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    • "The kinases IKK (IkB kinase) and JNK-1 (c-Jun N-terminal kinase 1) negatively regulate IRS-1 and IRS-2 by serine phosphorylation, inducing degradation of IRS proteins and inhibition of insulin receptor signaling.11,12 Increased IRS-1 serine phosphorylation is observed in insulin-resistant states.13,14 SOCS (suppressor of cytokine signaling) proteins compete with IRS proteins for binding sites on the insulin receptor, inhibit IRS tyrosine phosphorylation, and induce IRS-1 and IRS-2 degradation.15,16 "
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