Blockade of the Nuclear Factor-κB Pathway in the Endothelium Prevents Insulin Resistance and Prolongs Life Spans (original) (raw)
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Circulation, 2012
Background— Nuclear factor-κB (NF-κB) signaling plays critical roles in physiological and pathological processes such as responses to inflammation and oxidative stress. Methods and Results— To examine the role of endothelial NF-κB signaling in vivo, we generated transgenic mice expressing dominant-negative IκB under the Tie2 promoter/enhancer (E-DNIκB mice). These mice exhibited functional inhibition of NF-κB signaling specifically in endothelial cells. Although E-DNIκB mice displayed no overt phenotypic changes when young and lean, they were protected from the development of insulin resistance associated with obesity, whether diet- or genetics-induced. Obesity-induced macrophage infiltration into adipose tissue and plasma oxidative stress markers were decreased and blood flow and mitochondrial content in muscle and active-phase locomotor activity were increased in E-DNIκB mice. In addition to inhibition of obesity-related metabolic deteriorations, blockade of endothelial NF-κB sign...
Diet-induced obesity increases NF-κB signaling in reporter mice
2009
The nuclear factor (NF)-jB is a primary regulator of inflammatory responses and may be linked to pathology associated with obesity. We investigated the progression of NF-jB activity during a 12-week feeding period on a high-fat diet (HFD) or a low-fat diet (LFD) using NF-jB luciferase reporter mice. In vivo imaging of luciferase activity showed that NF-jB activity was higher in the HFD mice compared with LFD-fed mice. Thorax region of HFD females displayed fourfold higher activity compared with LFD females, while no such increase was evident in males. In male HFD mice, abdominal NF-jB activity was increased twofold compared with the LFD males, while females had unchanged NF-jB activity in the abdomen by HFD. HFD males, but not females, exhibited evident glucose intolerance during the study. In conclusion, HFD increased NF-jB activity in both female and male mice. However, HFD differentially increased activity in males and females. The moderate increase in abdomen of male mice may be linked to glucose intolerance.
Diet-induced obesity increases NF-kappaB signaling in reporter mice
Genes & nutrition, 2009
The nuclear factor (NF)-kappaB is a primary regulator of inflammatory responses and may be linked to pathology associated with obesity. We investigated the progression of NF-kappaB activity during a 12-week feeding period on a high-fat diet (HFD) or a low-fat diet (LFD) using NF-kappaB luciferase reporter mice. In vivo imaging of luciferase activity showed that NF-kappaB activity was higher in the HFD mice compared with LFD-fed mice. Thorax region of HFD females displayed fourfold higher activity compared with LFD females, while no such increase was evident in males. In male HFD mice, abdominal NF-kappaB activity was increased twofold compared with the LFD males, while females had unchanged NF-kappaB activity in the abdomen by HFD. HFD males, but not females, exhibited evident glucose intolerance during the study. In conclusion, HFD increased NF-kappaB activity in both female and male mice. However, HFD differentially increased activity in males and females. The moderate increase in...
2019
Obesity is associated with a state of chronic inflammation that is thought to be major contributor to disease and atherosclerosis. Many inflammatory pathways that contribute to the development of insulin resistance and atherosclerosis are regulated by IKKNF-κB signaling. Several studies during the past two decades have highlighted the key role of the IKK/NF-κB pathway in the induction and maintenance of the state of inflammation that underlies metabolic diseases. We addressed the stipulated role of IKKβ to produce proinflammatory cytokines in cultured human adipocytes using small molecule inhibitor. We hypothesized that IKK/NF-kB signaling plays a critical role in inflammatory pathway in human adipocytes which may subsequently contribute to insulin resistance and atherosclerosis. We have developed an effective protocol for deriving adipocytes from in vitro culture of pre-adipocytes and demonstrated upregulation of proinflammatory cytokines in this system. Our results show that IKK i...
Diabetes, 2015
Metabolic inflammation in the central nervous system might be causative for the development of over nutrition-induced metabolic syndrome and related disorders such as obesity, leptin- and insulin-resistance and type II diabetes. Here we investigated whether nutritive and genetic inhibition of the central IKKβ/NF-κB pathway in DIO- and leptin-deficient mice improves these metabolic impairments. A known prominent inhibitor of IKKβ/NF-κB signalling is the dietary flavonoid butein. We initially determined that oral, intraperitoneal and intracerebroventricular administration of this flavonoid improved glucose tolerance and hypothalamic insulin signalling. The dose-dependent glucose lowering capacity was profound regardless of whether obesity was caused by leptin deficiency or high fat diet. To confirm the apparent central role of IKKβ/NF-κB signalling in the control of glucose- and energy homeostasis we genetically inhibited this pathway in neurons of the arcuate nucleus, one key centre ...
Inflammation and the IKKβ/IκB/NF-κB axis in obesity-and diet-induced insulin resistance
International Journal of Obesity, 2003
Antidiabetic effects associated with salicylates have been known for years, although the underlying mechanisms were not understood. We have been reinvestigating these effects in the light of recent discoveries in the areas of signal transduction and insulin resistance. Our findings showed that signaling pathways leading to IkB kinase b (IKKb) and NF-kB are activated in insulinresponsive tissues of obese and high-fat-fed animals. Since activation correlates with the development of insulin resistance, we asked whether signaling through this might be involved in the pathogenesis of insulin resistance. Heterozygous gene deletion (Ikkb þ /À) or salicylates, working as IKKb inhibitors, improved insulin sensitivity in insulin-resistant rodent models. Furthermore, high doses of salicylates (aspirin or salicylate) improved insulin sensitivity in patients with type II diabetes. Our studies implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type II diabetes mellitus and identify the IKKb/ NF-kB pathway as a molecular mediator of insulin resistance and pharmacological target for insulin sensitization.
Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB
Nature Medicine, 2005
We show that NF-κB 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-κB in the liver of transgenic mice, designated LIKK, by selectively expressing constitutively active IKK-β 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-1β and TNF-α, 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-β. Hepatic expression of the IκBα 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-κB activation and downstream cytokine production. This causes insulin resistance both locally in liver and systemically.
Nuclear factor κB-inducing kinase activation as a mechanism of pancreatic β cell failure in obesity
The Journal of experimental medicine, 2015
The nuclear factor κB (NF-κB) pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic β cell dysfunction in the metabolic syndrome. Whereas canonical NF-κB signaling is well studied, there is little information on the divergent noncanonical NF-κB pathway in the context of pancreatic islet dysfunction. Here, we demonstrate that pharmacological activation of the noncanonical NF-κB-inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. We identify NIK as a critical negative regulator of β cell function, as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of noncanonical NF-κB components p100 to p52, and accumulation of RelB. TNF and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in...
Obesity, 2013
Objective: Central obesity and sub-clinical inflammation increase metabolic risk, this study examined the intracellular inflammatory pathways in adipose tissue (AT) that contribute to this risk. Design and Methods: This study therefore addressed the influence of NFjB and JNK activation in human abdominal subcutaneous (AbdSc) and omental (Om) AT, the effect of adiposity, T2DM status and the role of TNFa in vitro, using molecular biology techniques. Results: Our data showed NFjB activity is increased in Om AT versus AbdSc AT (P<0.01), which was reversed with respect to depot specific activation of JNK (P<0.01). However, T2DM status appeared to preferentially activate NFjB (P<0.001) over JNK. Furthermore, in vitro studies showed recombinant human (rh) TNFa treated AbdSc adipocytes increased NFjB activity over time (2-48 h, P<0.05) whilst JNK activity reduced (2 h, 4 h, P<0.05); inhibitor studies supported a preferential role for NFjB as a modulator of TNFa secretion. Conclusions: These studies suggest distinct changes in NFjB and JNK activation, dependent upon AT depot, adiposity and T2DM status, with in vitro use of rh TNFa leading to activation of NFjB. Consequently NFjB appears to play a central role in inflammatory mediated metabolic disease over JNK, highlighting NFjB as a potential key target for therapeutic intervention.
The Role of the Nrf2 Signaling in Obesity and Insulin Resistance
International Journal of Molecular Sciences
Obesity, a metabolic disorder characterized by excessive accumulation of adipose tissue, has globally become an increasingly prevalent disease. Extensive studies have been conducted to elucidate the underlying mechanism of the development of obesity. In particular, the close association of inflammation and oxidative stress with obesity has become increasingly evident. Obesity has been shown to exhibit augmented levels of circulating proinflammatory cytokines, which have been associated with the activation of pathways linked with inflammation-induced insulin resistance, a major pathological component of obesity and several other metabolic disorders. Oxidative stress, in addition to its role in stimulating adipose differentiation, which directly triggers obesity, is considered to feed into this pathway, further aggravating insulin resistance. Nuclear factor E2 related factor 2 (Nrf2) is a basic leucine zipper transcription factor that is activated in response to inflammation and oxida...