NFκB as a potent regulator of inflammation in human adipose tissue, influenced by depot, adiposity, T2DM status, and TNFα (original) (raw)
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A Macrophage NBR1-MEKK3 Complex Triggers JNK-Mediated Adipose Tissue Inflammation in Obesity
Cell Metabolism, 2014
The c-Jun NH(2)-terminal kinase (JNK) is a critical determinant of obesity-associated inflammation and glucose intolerance. The upstream mechanisms controlling this pathway are still unknown. Here we report that the levels of the PB1 domain-containing adaptor NBR1 correlated with the expression of proinflammatory molecules in adipose tissue from human patients with metabolic syndrome, suggesting that NBR1 plays a key role in adipose-tissue inflammation. We also show that NBR1 inactivation in the myeloid compartment impairs the function, M1 polarization, and chemotactic activity of macrophages; prevents inflammation of adipose tissue; and improves glucose tolerance in obese mice. Furthermore, we demonstrate that an interaction between the PB1 domains of NBR1 and the mitogen-activated kinase kinase 3 (MEKK3) enables the formation of a signaling complex required for the activation of JNK. Together, these discoveries identify an NBR1-MEKK3 complex as a key regulator of JNK signaling and adipose tissue inflammation in obesity. (A-F) Positive correlation between transcript levels of NBR1 and PPARg1 (A), PPARg2 (B), CD68 (C), CD163 (D), MIP-1 (E), and MCP-1 (F) in obese patients. See also Table S1.
Journal of Biological Chemistry, 2005
Lipid infusion and high fat feeding are established causes of systemic and adipose tissue insulin resistance. In this study, we treated 3T3-L1 adipocytes with a mixture of free fatty acids (FFAs) to investigate the molecular mechanisms underlying fat-induced insulin resistance. FFA treatment impaired insulin receptor-mediated signal transduction and decreased insulin-stimulated GLUT4 translocation and glucose transport.
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.
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...
OBM Hepatology and Gastroenterology
Background: A great number of inflammatory mediators and metabolic biomarkers have been shown to contribute to the development and progression of obesity-induced pathologies, including insulin resistance and non-alcoholic fatty liver disease (NAFLD). Many of those mediators are either targets or activators of Nuclear Factor-κappa B (NF-κB), which is a key transcription factor that plays a pivotal role in the homeostasis and regulation of inflammatory signaling pathways in the liver. Methods: Our study population consists of 50 morbidly obese patients undergoing planned bariatric surgery, during which biopsies were taken from the visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), skeletal muscle (SM), extramyocellular adipose tissue (EMAT) and the liver. We evaluated the differential protein expression of NF-κB, ERβ (Estrogen Receptor β), NFATc1 (Nuclear factor of activated T-cells) and PGC1a (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) by immunohistochemistry. Results: We found that NF-κB is the key biomarker in a complicated intra-and inter-tissue co-expression network that interconnects metabolic and immune signaling pathways. We also demonstrated a possible role in lipid metabolism and the development of skeletal muscle insulin resistance and non-alcoholic steatohepatitis (NASH). Conclusions: Our findings suggest that NF-κB may be the critical link between immune and metabolic pathways and could represent a future preventive and therapeutic target against obesity-induced metabolic diseases. We hope that our study will contribute to the better understanding of the complex inter-tissue connections that are disrupted in obesity and its associated comorbidities.
NF-κB is important for TNF-α-induced lipolysis in human adipocytes
Journal of Lipid Research, 2007
Tumor necrosis factor-a (TNF-a) promotes lipolysis in mammal adipocytes via the mitogen-activated protein kinase (MAPK) family, resulting in reduced expression/ function of perilipin (PLIN). The role of another pivotal intracellular messenger activated by TNF-a, nuclear factor-kB (NF-kB), has not been recognized. We explored the role of NF-kB in TNF-a-induced lipolysis of human fat cells. Primary cultures of human adipocytes were incubated in the presence of a cell-permeable peptide that inhibits NF-kB signaling (WP). Incubation with WP, but not with a biologically inactive peptide (MP), abolished the nuclear translocation of NF-kB and effectively abrogated TNF-a-induced lipolysis in a concentration-dependent manner. Western blot analysis demonstrated that although TNF-a per se reduced mainly PLIN protein expression, TNF-a in the presence of WP resulted in a pronounced combined reduction of both hormone-sensitive lipase (HSL) and PLIN protein. The expression of a set of other lipolytic or adipocyte-specific proteins was not affected. The regulation was presumably at the transcriptional level, because mRNA expression for HSL and PLIN was markedly reduced with TNF-a in the presence of NF-kB inhibition. This was confirmed in gene reporter assays using human PLIN and HSL promoter constructs. We conclude that in the presence of NF-kB inhibition, TNF-a-mediated lipolysis is reduced, which suggests that NF-kB is essential for retained human fat cell lipolysis.
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...
Adipocyte differentiation induces dynamic changes in NF- B expression and activity
AJP: Endocrinology and Metabolism, 2004
The adipocyte exerts an important role in energy homeostasis, both as depot for energy-rich triglycerides and as a source for metabolic hormones. Adipocytes also contribute to inflammation and the innate immune response. Although it can be physiologically beneficial to combine these two functions in a single cell type under some circumstances, the proinflammatory signals emanating from adipocytes in the obese state can have local and systemic effects that promote atherosclerosis and insulin resistance. The transcriptional machinery in the adipocyte that mediates these pro-inflammatory responses has remained poorly characterized to date. In particular, no information is currently available on the NF-κB family of transcription factors. Here, we show that adipogenesis is associated with changes in amount and subunit composition of the NF-κB complexes. NF-κB subunits p65 (RelA), p68 (RelB), and IκB are upregulated during fat cell differentiation. Correspondingly, basal NF-κB nuclear gel...