Troglitazone Antagonizes Tumor Necrosis Factor-α-induced Reprogramming of Adipocyte Gene Expression by Inhibiting the Transcriptional Regulatory Functions of NF-κB

Ruan, Hong; Pownall, Henry J.; Lodish, Harvey F.

doi:10.1074/jbc.m303141200

Cited by 174 publications

(142 citation statements)

References 59 publications

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“…Overexpression of DGAT correlates with increased TAG storage in adipose tissue, skeletal muscle and liver (62)(63)(64) . DGAT1 expression in adipocytes and adipose tissue is up-regulated by PPARg (65)(66)(67) . HFDfed Ap2-Dgat1 mice overexpressing DGAT1 in both macrophages and adipocytes became obese; however, they were protected from the associated metabolic and inflammatory perturbations.…”

Section: Fatty Acids and Adipose Tissue Macrophage Polarisationmentioning

confidence: 99%

Fats, inflammation and insulin resistance: insights to the role of macrophage and T-cell accumulation in adipose tissue

et al. 2011

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High-fat diet-induced obesity is associated with a chronic state of low-grade inflammation, which pre-disposes to insulin resistance (IR), which can subsequently lead to type 2 diabetes mellitus. Macrophages represent a heterogeneous population of cells that are instrumental in initiating the innate immune response. Recent studies have shown that macrophages are key mediators of obesity-induced IR, with a progressive infiltration of macrophages into obese adipose tissue. These adipose tissue macrophages are referred to as classically activated (M1) macrophages. They release cytokines such as IL-1β, IL-6 and TNFα creating a pro-inflammatory environment that blocks adipocyte insulin action, contributing to the development of IR and type 2 diabetes mellitus. In lean individuals macrophages are in an alternatively activated (M2) state. M2 macrophages are involved in wound healing and immunoregulation. Wound-healing macrophages play a major role in tissue repair and homoeostasis, while immunoregulatory macrophages produce IL-10, an anti-inflammatory cytokine, which may protect against inflammation. The functional role of T-cell accumulation has recently been characterised in adipose tissue. Cytotoxic T-cells are effector T-cells and have been implicated in macrophage differentiation, activation and migration. Infiltration of cytotoxic T-cells into obese adipose tissue is thought to precede macrophage accumulation. T-cell-derived cytokines such as interferon γ promote the recruitment and activation of M1 macrophages augmenting adipose tissue inflammation and IR. Manipulating adipose tissue macrophages/T-cell activity and accumulation in vivo through dietary fat modification may attenuate adipose tissue inflammation, representing a therapeutic target for ameliorating obesity-induced IR.

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Section: Fatty Acids and Adipose Tissue Macrophage Polarisationmentioning

confidence: 99%

Fats, inflammation and insulin resistance: insights to the role of macrophage and T-cell accumulation in adipose tissue

et al. 2011

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“…PPARg agonists downregulate the expression of TNFa in adipose tissue and improve TNFainduced desensitization to insulin action. 14 PPARg is expressed in a number of cell types in different tissues. It is not clear which of the cell types that express PPARg represents the most essential site of TZD action.…”

Section: Pparc Is the Primary Target Transcription Factor For Tzdsmentioning

confidence: 99%

Adiponectin: a relevant player in PPARγ-agonist-mediated improvements in hepatic insulin sensitivity?

2005

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The potent insulin-sensitizing effects of peroxisome proliferator-activated receptor g (PPARg) agonists are well established. However, it is still a matter of intense debate as to which tissue(s) represent the most critical sites of action for PPARg agonists, and what the relevant target genes are that ultimately mediate the improvements in insulin sensitivity. The cell type with the highest levels of PPARg is the adipocyte, and as such the adipocyte is an excellent candidate cell to look for critical mediators of PPARg agonist action. Adiponectin, an adipocyte-specific secretory protein, is upregulated in response to PPARg agonist exposure, and its serum levels consequently increase significantly. Genetic, pharmacological and clinical studies have demonstrated potent insulin-sensitizing effects of adiponectin. Here, we summarize the evidence that implicates adiponectin as a critical mediator of PPARg-agonist-mediated improvements in insulin sensitivity, particularly in the context of PPARg-agonistmediated enhancements of hepatic insulin sensitivity.

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“…NF-B activity is increased by either p65 overexpression or p50 knock-out. In the current study, the NF-B activity is enhanced in these approaches in two lines of transgenic mice (aP2-p65 mice and p50-KO mice).In cellular models, NF-B was shown to inhibit the differentiation and function of adipocytes in the signaling pathway of 17). The molecular mechanism is related to inhibition of PPAR␥ activity by NF-B.…”

mentioning

confidence: 95%

“…In cellular models, NF-B was shown to inhibit the differentiation and function of adipocytes in the signaling pathway of 17). The molecular mechanism is related to inhibition of PPAR␥ activity by NF-B.…”

mentioning

confidence: 99%

Uncoupling of Inflammation and Insulin Resistance by NF-κB in Transgenic Mice through Elevated Energy Expenditure

Tang

Zhang

Yin

et al. 2010

Journal of Biological Chemistry

135

103

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To study the metabolic activity of NF-B, we investigated phenotypes of two different mouse models with elevated NF-B activities. The transcriptional activity of NF-B is enhanced either by overexpression of NF-B p65 (RelA) in aP2-p65 mice or inactivation of NF-B p50 (NF-B1) through gene knock-out. In these models, energy expenditure was elevated in day and night time without a change in locomotion. The mice were resistant to adulthood obesity and diet-induced obesity without reduction in food intake. The adipose tissue growth and adipogenesis were inhibited by the elevated NF-B activity. Peroxisome proliferator-activator receptor ␥ expression was reduced by NF-B at the transcriptional level. The two models exhibited elevated inflammatory cytokines (tumor necrosis factor-␣ and interleukin-6) in adipose tissue and serum. However, insulin sensitivity was not reduced by the inflammation in the mice on a chow diet. On a high fat diet, the mice were protected from insulin resistance. The glucose infusion rate was increased more than 30% in the hyperinsulinemic-euglycemic clamp test. Our data suggest that the transcription factor NF-B promotes energy expenditure and inhibits adipose tissue growth. The two effects lead to prevention of adulthood obesity and dietary obesity. The energy expenditure may lead to disassociation of inflammation with insulin resistance. The study indicates that inflammation may prevent insulin resistance by eliminating lipid accumulation.The IKK␤ 2 /NF-B signaling pathway plays an important role in the control of inflammation, apoptosis, carcinogenesis, and oxidative stress (1). In this pathway, the serine kinase IKK␤ (IKK2) activates the transcription factor NF-B through phosphorylation of NF-B inhibitor (IB␣). In obesity research, the metabolic activity of IKK␤ was tested in the control of insulin sensitivity (2-4) or food intake in transgenic mice (5). In these studies, the IKK␤ activity was modified either globally or tissuespecifically in several major tissues/organs, such as the liver (3, 4), skeletal muscle (6), and brain (5). In these studies, the role of IKK␤ in the regulation of energy expenditure and adipose tissue growth was not examined. Although IKK␤ and NF-B activities are parallel in most cases, their activities are not identical (7). IKK␤ has NF-B-independent activities (7, 8). We investigated the metabolic activity of NF-B using the NF-B transgenic mice in the current study.NF-B activation is associated with energy expenditure in cachexia (9, 10). However, the cause/effect relationship has not been tested for NF-B/energy expenditure in transgenic models. NF-B is a transcription factor that regulates expression of a broad spectrum of genes. Its activity is found in many types of cells, including adipocytes and macrophages (1, 11). The common form of NF-B contains two subunits: p65 (RelA) and p50 (NF-B1). p65 contains the transactivation domain and mediates transcriptional activation of target genes. p50 usually inhibits the transcriptional activity of p65 (12), and the inhibiti...

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Troglitazone Antagonizes Tumor Necrosis Factor-α-induced Reprogramming of Adipocyte Gene Expression by Inhibiting the Transcriptional Regulatory Functions of NF-κB

Cited by 174 publications

References 59 publications

Fats, inflammation and insulin resistance: insights to the role of macrophage and T-cell accumulation in adipose tissue

Fats, inflammation and insulin resistance: insights to the role of macrophage and T-cell accumulation in adipose tissue

Adiponectin: a relevant player in PPARγ-agonist-mediated improvements in hepatic insulin sensitivity?

Uncoupling of Inflammation and Insulin Resistance by NF-κB in Transgenic Mice through Elevated Energy Expenditure

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