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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Available from: Jongsoon Lee, Oct 10, 2015
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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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    ABSTRACT: Abstract Context: Metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) are the emerging co-morbidities of skin inflammation. Occurrence of skin inflammation such as psoriasis is substantially higher in NAFLD patients than normal. Currently, there are no animal models to study the interaction between these co-morbidities. Objective: The present study seeks to develop a simple mouse model of NAFLD-enhanced skin inflammation and to study the effect of NAFLD on different parameters of skin inflammation. Materials and method: Metabolic syndrome and NAFLD were induced in C57BL/6 mice by feeding high-fat diet (HFD, 60% kcal) and high fructose liquid (HFL, 40% kcal) in drinking water. Skin inflammation was induced by repeated application of oxazolone (1% sensitization and repeated 0.5% challenge) in both normal and NAFLD mice and various parameters of skin inflammation and NAFLD were measured. Results: HFD and HFL diet induced obesity, hyperglycemia, hyperinsulinemia, and histological features of NAFLD in mice. Oxazolone challenge significantly increased ear thickness, ear weight, MPO activity, NF-κB activity, and histological features of skin inflammation in NAFLD mice as compared with normal mice. Overall, induction of oxazolone-induced skin inflammation was more prominent in NAFLD mice than normal mice. Hence, HFD and HFL diet followed by topical oxazolone application develops metabolic syndrome, NAFLD, and enhanced skin inflammation in mice. Discussion and conclusion: This simple model can be utilized to evaluate a therapeutic strategy for the treatment of metabolic syndrome and NAFLD with skin inflammation and also to understand the nexus between these co-morbidities.
    Pharmaceutical Biology 11/2014; 53(8):1-8. DOI:10.3109/13880209.2014.960944 · 1.24 Impact Factor
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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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    ABSTRACT: High-fat (HF) diet-induced obesity and insulin insensitivity are associated with inflammation, particularly in white adipose tissue (WAT). However, insulin insensitivity is apparent within days of HF feeding when gains in adiposity and changes in markers of inflammation are relatively minor. To investigate further the effects of HF diet, C57Bl/6J mice were fed either a low (LF) or HF diet for 3 days to 16 weeks, or fed the HF-diet matched to the caloric intake of the LF diet (PF) for 3 days or 1 week, with the time course of glucose tolerance and inflammatory gene expression measured in liver, muscle and WAT. HF fed mice gained adiposity and liver lipid steadily over 16 weeks, but developed glucose intolerance, assessed by intraperitoneal glucose tolerance tests (IPGTT), in two phases. The first phase, after 3 days, resulted in a 50% increase in area under the curve (AUC) for HF and PF mice, which improved to 30% after 1 week and remained stable until 12 weeks. Between 12 and 16 weeks the difference in AUC increased to 60%, when gene markers of inflammation appeared in WAT and muscle but not in liver. Plasma proteomics were used to reveal an acute phase response at day 3. Data from PF mice reveals that glucose intolerance and the acute phase response are the result of the HF composition of the diet and increased caloric intake respectively. Thus, the initial increase in glucose intolerance due to a HF diet occurs concurrently with an acute phase response but these effects are caused by different properties of the diet. The second increase in glucose intolerance occurs between 12 - 16 weeks of HF diet and is correlated with WAT and muscle inflammation. Between these times glucose tolerance remains stable and markers of inflammation are undetectable.
    PLoS ONE 08/2014; 9(8):e106159. DOI:10.1371/journal.pone.0106159 · 3.23 Impact Factor
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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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