Cai, D. et al. Local and systemic insulin resistance resulting from hepatic activation of IKK- and NF-B. 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: 28.05). 03/2005; 11(2):183-90. DOI: 10.1038/nm1166
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Jongsoon Lee, Aug 21, 2015
1 Follower
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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 · 1.34 Impact Factor
  • Source
    • "Several studies have suggested a relationship between TNF-a levels and obesity and insulin resistance [7] [8]. Interleukin-6 (IL-6) is another proinflammatory cytokine, which is induced by TNF-a, and its serum levels were found to be higher in patients with NAFLD and in animal models [9] [10]. It is also considered to have a close relation with liver diseases associated with alcohol [2] [11]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although understanding the relation between psychotic behavior and immune abnormalities has been the focus of research for many years, it remains to be elucidated whether the changes in cytokine levels are part of etiology or a result of the stress associated with the disorder. In accordance with previous studies on changes in cytokine levels due to metabolic changes and psychosis, we hypothesized that fatty liver may potentiate apomorphine-induced stereotypy in a rodent model and that a synthetic glucagon-like peptide-1 analog exenatide would ameliorate this effect. In this study, 18 male Sprague Dawley albino mature rats were used. We induced hepatosteatosis in these rats by feeding them with 30% fructose dissolved in drinking water for 8 weeks. The animals were divided into three groups, namely, the normal group, the intracerebroventricular (ICV) exenatide group, and the ICV NaCl group. Apomorphine-induced stereotypic behavior test was performed in all groups and the liver was removed for histopathological examination after all the rats were euthanized. In the nonalcoholic fatty liver (NAFL) group, stereotypy scores were significantly increased compared with the control group rats (p < 0.00001). A significant decrease in stereotypy scores were observed in the ICV exenatide group with NAFL when compared with the ICV saline group with NAFL (p < 0.005). In addition, brain malondialdehyde and tumor necrosis factor-α levels decreased in the ICV exenatide group. The results of this study showed that fatty liver enhances the effect of apomorphine on stereotypy, which was reversed by exenatide possibly by antioxidant and anti-inflammatory effects.
    The Kaohsiung Journal of Medical Sciences 06/2014; DOI:10.1016/j.kjms.2014.05.007 · 0.61 Impact Factor
  • Source
    • "Not surprisingly, these newly recruited inflammatory immune cells up-regulate and increase the activity of a surfeit of proinflammatory signaling molecules such as, inhibitor of nuclear factor kappa-B kinase subunit beta (IKKb) (Lumeng et al., 2007; Cai et al., 2005; Arkan et al., 2005), IKKe, janus kinase (JNK) (Solinas et al., 2007; Schneider et al., 2006; Han et al., 2013; Holzer et al., 2011; Hirosumi et al., 2002), mitogen-activated protein kinases (MAPK) (Wu et al., 2006), double-stranded RNA-dependent protein kinase (PKR) (Nakamura et al., 2010) and iNOS (Carvalheira et al., 2005; Ropelle et al., 2013; Foster et al., 2003) in metabolic tissues. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The control of energy homeostasis relies on robust neuronal circuits that regulate food intake and energy expenditure. Although the physiology of these circuits is well understood, the molecular and cellular response of this program to chronic diseases is still largely unclear. Hypothalamic inflammation has emerged as a major driver of energy homeostasis dysfunction in both obesity and anorexia. Importantly, this inflammation disrupts the action of metabolic signals promoting anabolism or supporting catabolism. In this review, we address the evidence that favors hypothalamic inflammation as a factor that resets energy homeostasis in pathological states.
    Molecular and Cellular Endocrinology 06/2014; 397(1-2). DOI:10.1016/j.mce.2014.06.005 · 4.24 Impact Factor
Show more