A PPAR agonist improves TNF-α-induced insulin resistance of adipose tissue in mice

2003 ◽  
Vol 309 (2) ◽  
pp. 419-424 ◽  
Author(s):  
M Shibasaki ◽  
K Takahashi ◽  
T Itou ◽  
H Bujo ◽  
Y Saito
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Ppar Agonist ◽  
Tnf Α

scholarly journals Adiponectin and other Adipocytokines as Predictors of Markers of Triglyceride-Rich Lipoprotein Metabolism

2005 ◽  
Vol 51 (3) ◽  
pp. 578-585 ◽  
Author(s):  
Dick C Chan ◽  
Gerald F Watts ◽  
Theodore WK Ng ◽  
Yoshiaki Uchida ◽  
Naohiko Sakai ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Independent Predictor ◽  
Lipoprotein Metabolism ◽  
Bioelectrical Impedance ◽  
Apo B ◽  
Nonesterified Fatty Acids ◽  
Plasma Adiponectin ◽  
Tnf Α ◽  
Triglyceride Rich Lipoprotein

Abstract Background: Adipocytokines are bioactive peptides that may play an important role in the regulation of glucose and lipid metabolism. In this study, we investigated the association of plasma adipocytokine concentrations with markers of triglyceride-rich lipoprotein (TRL) metabolism in men. Methods: Fasting adiponectin, leptin, resistin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), apolipoprotein (apo) B-48, apo C-III, and remnant-like particle (RLP)-cholesterol concentrations were measured by immunoassays and insulin resistance by homeostasis assessment (HOMA) score in 41 nondiabetic men with a body mass index of 22–35 kg/m2. Visceral and subcutaneous adipose tissue masses (ATMs) were determined by magnetic resonance imaging and total ATM by bioelectrical impedance. Results: In univariate regression, plasma adiponectin and leptin concentrations were inversely and directly associated with plasma apoB-48, apoC-III, RLP-cholesterol, triglycerides, VLDL-apoB, and VLDL-triglycerides (P <0.05). Resistin, IL-6, and TNF-α were not significantly associated with any of these variables, except for a direct correction between apoC-III and IL-6 (P <0.05). In multivariate regression including HOMA, age, nonesterified fatty acids, and adipose tissue compartment, adiponectin was an independent predictor of plasma apoB-48 (β coefficient = −0.354; P = 0.048), apoC-III (β coefficient = −0.406; P = 0.012), RLP-cholesterol (β coefficient = −0.377; P = 0.016), and triglycerides (β coefficient = −0.374; P = 0.013). By contrast, leptin was not an independent predictor of these TRL markers. Plasma apoB-48, apoC-III, RLP-cholesterol, and triglycerides were all significantly and positively associated with plasma insulin, HOMA, and visceral, subcutaneous, and total ATMs (P <0.05). Conclusions: These data suggest that the plasma adiponectin concentration may not only link abdominal fat, insulin resistance, and dyslipidemia, but may also exert an independent role in regulating TRL metabolism.

TWEAK prevents TNF-α-induced insulin resistance through PP2A activation in human adipocytes

2013 ◽  
Vol 305 (1) ◽  
pp. E101-E112 ◽  
Author(s):  
Ana Vázquez-Carballo ◽  
Victòria Ceperuelo-Mallafré ◽  
Matilde R. Chacón ◽  
Elsa Maymó-Masip ◽  
Margarita Lorenzo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Signaling ◽  
Visceral Fat ◽  
Molecular Mechanisms ◽  
Physiological Role ◽  
Metabolic Effects ◽  
Human Adipocytes ◽  
Fat Depots ◽  
Tnf Α

Visceral fat is strongly associated with insulin resistance. Obesity-associated adipose tissue inflammation and inflammatory cytokine production are considered key mediators of insulin signaling inhibition. TWEAK is a relatively new member of the TNF cytokine superfamily, which can exist as full length membrane-associated (mTWEAK) and soluble (sTWEAK) isoforms. Although TWEAK has been shown to have important functions in chronic inflammatory diseases its physiological role in adipose tissue remains unresolved. In this study, we explore the molecular mechanisms involved in the modulation of TNF-α-induced effects on insulin sensitivity by sTWEAK in a human visceral adipose cell line and also in primary human adipocytes obtained from visceral fat depots. Our data reveal that sTWEAK ameliorates TNF-α-induced insulin resistance on glucose uptake, GLUT4 translocation and insulin signaling without affecting other metabolic effects of TNF-α such as lipolysis or apoptotis. Co-immunoprecipitation experiments in adipose cells revealed that pretreatment with sTWEAK specifically inhibits TRAF2 association with TNFR1, but not with TNFR2, which mediates insulin resistance. However, sTWEAK does not affect other downstream molecules activated by TNF-α, such as TAK1. Rather, sTWEAK abolishes the stimulatory effect of TNF-α on JNK1/2, which is directly involved in the development of insulin resistance. This is associated with an increase in PP2A activity upon sTWEAK treatment. Silencing of the PP2A catalytic subunit gene overcomes the dephosphorylation effect of sTWEAK on JNK1/2, pointing to PP2A as a relevant mediator of sTWEAK-induced JNK inactivation. Overall, our data reveal a protective role of TWEAK in glucose homeostasis and identify PP2A as a new driver in the modulation of TNF-α signaling by sTWEAK.

scholarly journals Increased Subcutaneous and Epicardial Adipose Tissue Production of Proinflammatory Cytokines in Cardiac Surgery Patients: Possible Role in Postoperative Insulin Resistance

2006 ◽  
Vol 91 (11) ◽  
pp. 4620-4627 ◽  
Author(s):  
Jaromir Kremen ◽  
Marketa Dolinkova ◽  
Jana Krajickova ◽  
Jan Blaha ◽  
Katerina Anderlova ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Cardiac Surgery ◽  
Mrna Expression ◽  
Proinflammatory Cytokines ◽  
Epicardial Adipose Tissue ◽  
Monocyte Chemoattractant Protein 1 ◽  
Elective Cardiac Surgery ◽  
Tnf Α ◽  
History Of

Abstract Context: Hyperglycemia and insulin resistance frequently occur in critically ill patients even without a history of diabetes. Objective: Our objective was to study the role of adipose tissue hormonal production in the development of insulin resistance in cardiac surgery patients. Participants, Interventions, and Settings: Fifteen patients with elective cardiac surgery underwent blood sampling before, at the end, and 6, 12, 24, 48, and 120 h after the end of their operation. Epicardial and sc adipose tissue sampling was done at the beginning and at the end of surgery in the Department of Cardiac Surgery. Main Outcome Measures: We measured serum concentrations and sc and epicardial adipose tissue mRNA expression of IL-6, monocyte chemoattractant protein-1 (MCP-1), TNF-α, leptin, resistin, and adiponectin and sc and epicardial adipose tissue mRNA expression of CD14, CD45, and CD68. Results: The rate of insulin infusion required to maintain euglycemia increased up to 7-fold 12 h after the operation, suggesting the development of insulin resistance. Serum IL-6 levels increased 43-fold 12 h after surgery. MCP-1 peaked 6-fold at the end of surgery. Smaller peaks of TNF-α and leptin appeared 6 and 12 h after surgery, respectively. Resistin levels peaked 4-fold 24 h after surgery, but adiponectin levels were not significantly affected. TNF-α and CD45 mRNA expression increased markedly during the operation in sc adipose tissue. IL-6, resistin, and MCP-1 mRNA expression increased in both sc and epicardial adipose tissue. Leptin, adiponectin, CD14, and CD68 mRNA expression did not change significantly. Conclusions: Both sc and epicardial adipose tissue is a source of proinflammatory cytokines in cardiac surgery patients and may contribute to the development of postoperative insulin resistance.

scholarly journals A Fish Oil Diet Does Not Reverse Insulin Resistance despite Decreased Adipose Tissue TNF-α Protein Concentration in ApoE-3*Leiden Mice

2003 ◽  
Vol 133 (11) ◽  
pp. 3350-3355 ◽  
Author(s):  
Martin Muurling ◽  
Ronald P. Mensink ◽  
Hanno Pijl ◽  
Johannes A. Romijn ◽  
Louis M. Havekes ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Fish Oil ◽  
Protein Concentration ◽  
Tnf Α ◽  
Fish Oil Diet

scholarly journals Associations between insulin resistance and TNF-α in plasma, skeletal muscle and adipose tissue in humans with and without type 2 diabetes

Diabetologia ◽  
2007 ◽  
Vol 50 (12) ◽  
pp. 2562-2571 ◽  
Author(s):  
P. Plomgaard ◽  
A. R. Nielsen ◽  
C. P. Fischer ◽  
O. H. Mortensen ◽  
C. Broholm ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Tnf Α

Circulating resistin in lean, obese, and insulin-resistant mouse models: lack of association with insulinemia and glycemia

2005 ◽  
Vol 288 (3) ◽  
pp. E625-E632 ◽  
Author(s):  
Jennifer H. Lee ◽  
John W. Bullen ◽  
Violeta L. Stoyneva ◽  
Christos S. Mantzoros
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Mrna Expression ◽  
Mouse Models ◽  
Uncoupling Protein ◽  
High Fat ◽  
Resistant Mouse ◽  
Brown Adipose ◽  
Tnf Α ◽  
Resistin Mrna

Resistin is an adipocyte-secreted hormone proposed to link obesity with insulin resistance and diabetes, but no previous study has performed a joint quantitative evaluation of white adipose tissue (WAT) resistin mRNA expression and serum levels in relation to insulinemia and glycemia in mice. We have thus comparatively assessed WAT resistin mRNA expression and serum resistin levels in lean C57BL/6J mice and various mouse models of obesity, including diet-induced obese (DIO) C57BL/6J mice, high fat-fed TNF-α−/− mice, and brown adipose tissue (BAT)-deficient uncoupling protein-diphtheria toxin A chain (UCP1-DTA) mice. We also studied whether treatment with the weight-reducing and insulin-sensitizing compounds, MTII, an α-melanocyte-stimulating hormone analog, or CNTFAx15, a ciliary neurotrophic factor analog, alters resistin mRNA expression and/or circulating levels in lean and DIO C57BL/6J mice. We find that resistin mRNA expression is similar in DIO and lean C57BL/6J mice, as well as in TNF-α−/− and wild-type (WT) mice. Circulating resistin levels, however, are higher in DIO C57BL/6J, high fat-fed TNF-α−/−, and UCP1-DTA mice compared with lean controls. Moreover, although resistin mRNA expression is upregulated by MTII treatment for 24 h and downregulated by CNTFAx15 treatment for 3 or 7 days, circulating resistin levels are not altered by MTII or CNTFAx15 treatment. In addition, serum resistin levels, but not resistin mRNA expression levels, are correlated with body weight, and neither resistin mRNA expression nor serum resistin levels are correlated with serum insulin or glucose levels. We conclude that transcriptional regulation of resistin in WAT does not correlate with circulating resistin levels and that circulating resistin is unlikely to play a major endocrine role in insulin resistance or glycemia in mice.

scholarly journals Brown Fat Lipoatrophy and Increased Visceral Adiposity through a Concerted Adipocytokines Overexpression Induces Vascular Insulin Resistance and Dysfunction

Endocrinology ◽  
2012 ◽  
Vol 153 (3) ◽  
pp. 1242-1255 ◽  
Author(s):  
Almudena Gómez-Hernández ◽  
Yolanda F. Otero ◽  
Natalia de las Heras ◽  
Óscar Escribano ◽  
Victoria Cachofeiro ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Vascular Dysfunction ◽  
Nuclear Factor Κb ◽  
Brown Fat ◽  
Visceral Adiposity ◽  
Inflammatory Activity ◽  
Nuclear Factor ◽  
Antibody Treatment ◽  
Tnf Α

In this study, we analyzed the role played by concerted expression of adipocytokines associated with brown fat lipoatrophy and increased visceral adiposity on triggering vascular insulin resistance and dysfunction in brown adipose tissue (BAT) insulin receptor knockout (BATIRKO) mice. In addition, we assessed whether vascular insulin resistance may aggravate vascular damage. The 52-wk-old, but not 33-wk-old, BATIRKO mice had a significant decrease of BAT mass associated with a significant increase of visceral white adipose tissue (WAT) mass, without changes in body weight. Brown fat lipoatrophy and increased visceral adiposity enhanced the concerted expression of adipocytokines (TNF-α, leptin, and plasminogen activator inhibitor 1) and nuclear factor-κB binding activity in BAT and visceral WAT, mainly in the gonadal depot, and aorta. Although those mice showed insulin sensitivity in the liver and skeletal muscle, insulin signaling in WAT (gonadal depot) and aorta was markedly impaired. Treatment with anti-TNF-α antibody impaired the inflammatory activity in visceral adipose tissue, attenuated insulin resistance in WAT and aorta and induced glucose tolerance. Finally, 52-wk-old BATIRKO mice showed vascular dysfunction, macrophage infiltration, oxidative stress, and a significant increase of gene markers of endothelial activation and inflammation, the latter effect being totally reverted by anti-TNF-α antibody treatment. Our results suggest that brown fat lipoatrophy and increased visceral adiposity through the concerted overexpression of cytoadipokines induces nuclear factor-κB-mediated inflammatory signaling, vascular insulin resistance, and vascular dysfunction. Inhibition of inflammatory activity by anti-TNF-α antibody treatment attenuates vascular insulin resistance and impairs gene expression of vascular dysfunction markers.

scholarly journals Sulfasalazine and BAY 11-7082 Interfere with the Nuclear Factor-κB and IκB Kinase Pathway to Regulate the Release of Proinflammatory Cytokines from Human Adipose Tissue and Skeletal Muscle in Vitro

Endocrinology ◽  
2005 ◽  
Vol 146 (3) ◽  
pp. 1491-1497 ◽  
Author(s):  
Martha Lappas ◽  
Kirin Yee ◽  
Michael Permezel ◽  
Gregory E. Rice
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Human Adipose Tissue ◽  
Nuclear Factor Κb ◽  
Binding Activity ◽  
Dna Binding Activity ◽  
Iκb Kinase ◽  
Β Protein ◽  
Tnf Α

There is much evidence to indicate a role for adipocytokines in insulin resistance and/or type 2 diabetes mellitus. In experimental models, oral salicylates, through their ability to interfere with the nuclear factor-κB (NF-κB) transcription pathway, have been demonstrated to reverse insulin resistance. The aim of this study was to investigate whether NF-κB regulates the release of adipocytokines in human adipose tissue and skeletal muscle. Human sc adipose tissue and skeletal muscle (obtained from normal pregnant women) were incubated in the absence (control) or presence of two NF-κB inhibitors sulfasalazine (1.25, 2.5, and 5 mm) and BAY 11-7082 (25, 50, and 100 μm). After an 18-h incubation, the tissues were collected, and NF-κB p65 DNA-binding activity and IκB kinase (IKK-β) and insulin receptor-β protein expression were assessed by ELISA and Western blotting, respectively. The incubation medium was collected, and the release of TNF-α, IL-6, IL-8, resistin, adiponectin, and leptin was quantified by ELISA. Treatment of adipose tissue and skeletal muscle with sulfasalazine and BAY 11-7082 significantly inhibited the release of IL-6, IL-8, and TNF-α; NF-κB p65 DNA-binding activity; and IKK-β protein expression (P < 0.05, by Newman-Keuls test). There was no effect of sulfasalazine and BAY 11-7082 on resistin, adiponectin, or leptin release. Both sulfasalazine and BAY 11-7082 increased the adipose tissue and skeletal muscle expression of insulin receptor-β. The data presented in this study demonstrate that the IKK-β/NF-κB transcription pathway is a key regulator of IL-6, IL-8, and TNF-α release from adipose tissue and skeletal muscle. Control of the IKK-β/NF-κB pathway may therefore provide an alternative therapeutic strategy for regulating aberrant cytokine release and thereby alleviating insulin resistance in type 2 diabetes mellitus.

scholarly journals Circulating white blood cell count and measures of adipose tissue inflammation predict higher 24-h energy expenditure

2010 ◽  
Vol 162 (2) ◽  
pp. 275-280 ◽  
Author(s):  
Jianying He ◽  
Duc Son Le ◽  
Xiaoyuan Xu ◽  
Michael Scalise ◽  
Anthony W Ferrante ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Energy Expenditure ◽  
Blood Cell ◽  
Cell Count ◽  
Subclinical Inflammation ◽  
Blood Cell Count ◽  
Markers Of Inflammation ◽  
Tnf Α ◽  
Pai 1

ObjectiveEnergy expenditure (EE) and measures of inflammation increase with adiposity, and this obesity-induced chronic and subclinical inflammation was extensively reported to be a cause of insulin resistance. However, whether subclinical inflammation has a role in increasing EE, which may be at the cost of developing insulin resistance, is not clear.MethodsWe investigated the association between circulating white blood cell count (WBC) in a population of Native Americans (n=243) with measurement of EE in a respiratory chamber, and in a subset of the same population (n=34), with gene expression measures of inflammation in subcutaneous abdominal adipose tissue (SAAT). All subjects were healthy on oral glucose tolerance test. Statistically, nonnormally distributed variables were logarithmically transformed before analyses to approximate normal distributions.ResultsWBC was associated with 24-h EE adjusted for age, sex, fat-free mass, and fat mass (r=0.13, P=0.04). In SAAT, tumor necrosis factor-α (TNF-α), shown as log10-transformed TNF-α (r=0.36, P=0.05), and plasminogen activator inhibitor-1 (PAI-1), shown as log10-transformed PAI-1 (lPAI-1; r=0.41, P=0.02), expressions were also positively correlated with adjusted 24-h EE. lPAI-1 was also correlated with adjusted sleep EE (r=0.34, P=0.07).ConclusionsIn conclusion, circulating markers of inflammation (WBC) and markers of inflammation within adipose tissue (TNF-α and PAI-1) are positively associated with EE, indicating a role of chronic subclinical inflammation in the regulation of metabolic rate.

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