scholarly journals Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance

2016 ◽  
Vol 2 (3) ◽  
pp. e1501332 ◽  
Author(s):  
Sachiko Nishimoto ◽  
Daiju Fukuda ◽  
Yasutomi Higashikuni ◽  
Kimie Tanaka ◽  
Yoichiro Hirata ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Bone Marrow ◽  
Adipose Tissue ◽  
Visceral Obesity ◽  
Sterile Inflammation ◽  
Model Assessment ◽  
Wild Type ◽  
Exogenous Dna ◽  
Monocyte Chemoattractant Protein 1 ◽  
Macrophage Accumulation

Obesity stimulates chronic inflammation in adipose tissue, which is associated with insulin resistance, although the underlying mechanism remains largely unknown. Here we showed that obesity-related adipocyte degeneration causes release of cell-free DNA (cfDNA), which promotes macrophage accumulation in adipose tissue via Toll-like receptor 9 (TLR9), originally known as a sensor of exogenous DNA fragments. Fat-fed obese wild-type mice showed increased release of cfDNA, as determined by the concentrations of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in plasma. cfDNA released from degenerated adipocytes promoted monocyte chemoattractant protein-1 (MCP-1) expression in wild-type macrophages, but not in TLR9-deficient (Tlr9−/−) macrophages. Fat-fed Tlr9−/− mice demonstrated reduced macrophage accumulation and inflammation in adipose tissue and better insulin sensitivity compared with wild-type mice, whereas bone marrow reconstitution with wild-type bone marrow restored the attenuation of insulin resistance observed in fat-fed Tlr9−/− mice. Administration of a TLR9 inhibitory oligonucleotide to fat-fed wild-type mice reduced the accumulation of macrophages in adipose tissue and improved insulin resistance. Furthermore, in humans, plasma ssDNA level was significantly higher in patients with computed tomography–determined visceral obesity and was associated with homeostasis model assessment of insulin resistance (HOMA-IR), which is the index of insulin resistance. Our study may provide a novel mechanism for the development of sterile inflammation in adipose tissue and a potential therapeutic target for insulin resistance.

scholarly journals Abdominal adipocyte populations in women with visceral obesity

2016 ◽  
Vol 174 (2) ◽  
pp. 227-239 ◽  
Author(s):  
Andréanne Michaud ◽  
Sofia Laforest ◽  
Mélissa Pelletier ◽  
Mélanie Nadeau ◽  
Serge Simard ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Visceral Obesity ◽  
Resistance Index ◽  
Small Cells ◽  
Central Feature ◽  
Model Assessment ◽  
Insulin Resistance Index ◽  
Visceral Adipose

BackgroundVisceral obesity is independently related to numerous cardiometabolic alterations, with adipose tissue dysfunction as a central feature.ObjectiveTo examine whether omental (OM) and subcutaneous (SC) adipocyte size populations in women relate to visceral obesity, cardiometabolic risk factors and adipocyte lipolysis independent of total adiposity.Design and methodsOM and SC fat samples were obtained during gynecological surgery in 60 women (mean age, 46.1±5.9 years; mean BMI, 27.1±4.5 kg/m2(range, 20.3–41.1 kg/m2)). Fresh samples were treated with osmium tetroxide and were analyzed with a Multisizer Coulter. Cell size distributions were computed for each sample with exponential and Gaussian function fits.ResultsComputed tomography-measured visceral fat accumulation was the best predictor of larger cell populations as well as the percentage of small cells in both OM and SC fat (P<0.0001 for all). Accordingly, women with visceral obesity had larger cells in the main population and higher proportion of small adipocytes independent of total adiposity (P≤0.05). Using linear regression analysis, we found that women characterized by larger-than-predicted adipocytes in either OM or SC adipose tissue presented higher visceral adipose tissue area, increased percentage of small cells and homeostasis model assessment insulin resistance index as well as higher OM adipocyte isoproterenol-, forskolin- and dbcAMP-stimulated lipolysis compared to women with smaller-than-predicted adipocytes, independent of total adiposity (P≤0.05).ConclusionExcess visceral adipose tissue accumulation is a strong marker of both adipocyte hypertrophy and increased number of small cells in either fat compartment, which relates to higher insulin resistance index and lipolytic response, independent of total adiposity.

Investigating the relationship between insulin resistance and adipose tissue in a randomized Tehrani population

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Jalaledin Mirzay Razzaz ◽  
Hossein Moameri ◽  
Zahra Akbarzadeh ◽  
Mohammad Ariya ◽  
Seyed ali Hosseini ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Body Fat ◽  
Odds Ratio ◽  
Cross Sectional Study ◽  
Model Assessment ◽  
Fasting Insulin ◽  
Cross Sectional ◽  
Body Fat Percent ◽  
The Relationship

Abstract Objectives Insulin resistance is the most common metabolic change associated with obesity. The present study aimed to investigate the relationship between insulin resistance and body composition especially adipose tissue in a randomized Tehrani population. Methods This study used data of 2,160 individuals registered in a cross-sectional study on were randomly selected from among subjects who were referred to nutrition counseling clinic in Tehran, from April 2016 to September 2017. Insulin resistance was calculated by homeostasis model assessment formula. The odds ratio (95% CI) was calculated using logistic regression models. Results The mean age of the men was 39 (±10) and women were 41 (±11) (the age ranged from 20 to 50 years). The risk of increased HOMA-IR was 1.03 (95% CI: 1.01–1.04) for an increase in one percent of Body fat, and 1.03 (95% CI: 1.00–1.05) for an increase in one percent of Trunk fat. Moreover, the odds ratio of FBS for an increase in one unit of Body fat percent and Trunk fat percent increased by 1.05 (adjusted odds ratio [95% CI: 1.03, 1.06]) and 1.05 (95% CI: 1.02, 1.08). Also, the risk of increased Fasting Insulin was 1.05 (95% CI: 1.03–1.07) for an increase in one unit of Body fat percent, and 1.05 (95% CI: 1.02–1.08) for an increase in one unit of Trunk fat percent. Conclusions The findings of the present study showed that there was a significant relationship between HOMA-IR, Fasting blood sugar, Fasting Insulin, and 2 h Insulin with percent of Body fat, percent of Trunk fat.

scholarly journals Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance

2003 ◽  
Vol 149 (4) ◽  
pp. 331-335 ◽  
Author(s):  
JV Silha ◽  
M Krsek ◽  
JV Skrha ◽  
P Sucharda ◽  
BL Nyomba ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Mass Index ◽  
Adipose Tissue ◽  
Statistical Significance ◽  
Model Assessment ◽  
Fasting Insulin ◽  
Homeostasis Model Assessment ◽  
Glucose Levels ◽  
Obese Subjects ◽  
The Relationship

OBJECTIVE: Adipose tIssue regulates insulin sensitivity via the circulating adipocytokines, leptin, resistin and adiponectin. The objective of this study was to compare the levels of resistin, adiponectin and leptin in lean and obese subjects and determine the relationship between circulating adipocytokines and insulin resistance. METHODS: We examined plasma levels of resistin, adiponectin and leptin in 17 lean subjects with a mean body mass index (BMI) of approximately 23 and 34 non-diabetic obese individuals with a mean BMI approximately 33. Insulin resistance was assessed using the homeostasis model assessment ratio (HOMA-R) formula derived from fasting insulin and glucose levels. RESULTS: Resistin levels were not significantly different between the two groups but were significantly higher in women compared with men, 35.4+/-6.5 (s.e.) vs 15.4+/-2.9 microg/L, P<0.01. Resistin did not correlate with BMI but did significantly correlate with HOMA-R, P<0.01, and this correlation remained significant after adjustment for gender and BMI. Adiponectin levels were significantly lower in obese compared with lean subjects, P<0.005, and higher in women, P<0.001, but showed no significant correlation with HOMA-R. Leptin levels were significantly higher in obese subjects and women and correlated with HOMA-R and resistin. DISCUSSION: In this small group of patients we demonstrated that insulin resistance correlated most strongly with leptin levels. A significant correlation between resistin levels and insulin resistance was also observed. Although a similar trend was apparent for adiponectin, the correlation with insulin resistance did not achieve statistical significance.

scholarly journals Complement Factor C3 Methylation and mRNA Expression Is Associated to BMI and Insulin Resistance in Obesity

Genes ◽  
2018 ◽  
Vol 9 (8) ◽  
pp. 410 ◽  
Author(s):  
Daniel Castellano-Castillo ◽  
Isabel Moreno-Indias ◽  
Jose Carlos Fernandez-Garcia ◽  
Mercedes Clemente-Postigo ◽  
Manuel Castro-Cabezas ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Dna Methylation ◽  
Adipose Tissue ◽  
Messenger Rna ◽  
Density Lipoprotein ◽  
Complement Factor ◽  
Mrna Levels ◽  
Model Assessment ◽  
Tissue Samples ◽  
Obese Class

Epigenetic marks, and especially DNA methylation, are becoming an important factor in obesity, which could help to explain its etiology and associated comorbidities. Adipose tissue, now considered as an important endocrine organ, produces complement system factors. Complement component 3 (C3) turns out to be an important protein in metabolic disorders, via either inflammation or the C3 subproduct acylation stimulating protein (ASP) which directly stimulates lipid storage. In this study, we analyze C3 DNA methylation in adipose tissue from subjects with a different grade of obesity. Adipose tissue samples were collected from subjects with a different degree of obesity determined by their body mass index (BMI) as: Overweight subjects (BMI ≥ 25 and <30), obese class 1/2 subjects (BMI ≥ 30 and <40) and obese class 3 subjects (BMI ≥ 40). C3 DNA methylation was measured for 7 CpGs by pyrosequencition using the Pyromark technology (Qiagen, Madrid Spain). C3 messenger RNA (mRNA) levels were analyzed by pre-designed Taqman assays (Applied biosystems, Foster City, CA, USA) and ASP/C3a was measured using a ELISA kit. The data were analyzed using the statistic package SPSS. C3 DNA methylation levels were lower in the morbid obese group. Accordingly, C3 methylation correlated negatively with BMI and leptin. However, C3 mRNA levels were more associated with insulin resistance, and positive correlations with insulin, glucose and homeostasis model assessment-estimated insulin resistance (HOMA-IR) existed. ASP correlated negatively with high density lipoprotein (HDL) cholesterol. C3 methylation levels were associated to adiposity variables, such as BMI and leptin, while the C3 mRNA levels were associated to glucose metabolism.

scholarly journals Elevated serum uric acid is a facilitating mechanism for insulin resistance mediated accumulation of visceral adipose tissue

2020 ◽  
Author(s):  
Luisa Fernández-Chirino ◽  
Neftali Eduardo Antonio-Villa ◽  
Arsenio Vargas-Vázquez ◽  
Paloma Almeda-Valdés ◽  
Donají Gómez-Velasco ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Uric Acid ◽  
Serum Uric Acid ◽  
Visceral Adipose Tissue ◽  
Visceral Obesity ◽  
Causal Mechanism ◽  
Mediation Analyses ◽  
Bidirectional Relationship ◽  
Visceral Adipose

BACKGROUND: Serum uric acid (SUA) has a relationship with cardiometabolic conditions such as insulin resistance (IR) and visceral adipose tissue (VAT) accumulation. Here, we aimed to clarify the nature of this relationship and the underlying causality mechanism. METHODS: We conducted a population-based cross-sectional study comprising 8,504 subjects joining both NHANES 2003-2004 and 2011-2012 cycles and ENSANUT Medio Camino 2016. We performed mixed effects linear regression models using HOMA2-IR, adipoIR, and METS-VF as indicators of IR and VAT accumulation. Furthermore, we performed mediation analyses to assess a potential causal mechanism and ROC curves to establish cut-off points for identification of IR and visceral obesity using SUA. Finally, with an additional dataset comprised of 226 subjects with both euglycemic hyperinsulinemic clamp (EHC) and dual X-ray absorptiometry (DXA) measurements for IR and VAT accumulation, we performed a network of confirmatory mediation analyses. RESULTS:We found that SUA has a mediating role inside the bidirectional relationship between IR and visceral obesity, and it is part of an underlying causality mechanism which includes adiponectin. The proportion of the mechanism mediated by SUA is greater when stated that IR (in either peripheral or adipose tissue) leads to VAT accumulation (14.90%[13.20%-17.00%] and 15.54%[13.61% - 18.00%] to 4.88%[3.06%-7.00%] and 8.13%[5.91% - 10.00%]) instead of the opposite direction. This result was confirmed by mediation analyses using gold-standard measurements. CONCLUSIONS:Elevated SUA acts as mediator inside the bidirectional relationship between IR andVAT accumulation. Its role appears to be larger when considering adipose tissue IR as the promoter for VAT accumulation.

scholarly journals The Relationship between Epicardial Adipose Tissue Thickness and Serum Interleukin-17a Level in Patients with Isolated Metabolic Syndrome

Biomolecules ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 97 ◽  
Author(s):  
Esra Demir ◽  
Nazmiye Harmankaya ◽  
İrem Kıraç Utku ◽  
Gönül Açıksarı ◽  
Turgut Uygun ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Epicardial Adipose Tissue ◽  
Control Group ◽  
Model Assessment ◽  
Tissue Thickness ◽  
The Metabolic Syndrome ◽  
Epicardial Adipose Tissue Thickness ◽  
The Relationship

In this study, it was aimed to investigate the relationship between the epicardial adipose tissue thickness (EATT) and serum IL-17A level insulin resistance in metabolic syndrome patients. This study enrolled a total of 160 subjects, of whom 80 were consecutive patients who applied to our outpatient clinic and were diagnosed with metabolic syndrome, and the other 80 were consecutive patients who were part of the control group with similar age and demographics in whom the metabolic syndrome was excluded. The metabolic syndrome diagnosis was made according to International Diabetes Federation (IDF)-2005 criteria. EATT was measured with transthoracic echocardiography (TTE) in the subjects. IL-17A serum levels were determined using the ELISA method. Fasting blood glucose, HDL, triglyceride, and fasting insulin levels were significantly higher in the metabolic syndrome group compared to the control group. In addition, the metabolic syndrome group had significantly higher high-sensitivity C-reactive protein (hs-CRP) and Homeostatic Model Assessment Insulin Resistance (HOMA-IR) levels than the control group. Similarly, serum IL-17A levels were significantly elevated in the metabolic syndrome group compared to the control group statistically (p < 0.001). As well, EATT was higher in the metabolic syndrome than the control group. Conclusion: By virtue of their proinflammatory properties, EATT and IL-17 may play an important role in the pathogenesis of the metabolic syndrome.

scholarly journals Visfatin levels in non-obese, obese, and insulin resistant adolescents

2017 ◽  
Vol 56 (5) ◽  
pp. 291
Author(s):  
Indra Ihsan ◽  
Eka Agustia Rini ◽  
Rismawati Yaswir
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Serum Insulin ◽  
Enzyme Linked Immunosorbent Assay ◽  
Model Assessment ◽  
Fasting Serum ◽  
Obese Adolescents ◽  
Insulin Resistant ◽  
Resistant Group ◽  
Visfatin Level

Background Adipose tissue is not merely a site for energy storage, but is also the largest endocrine organ, secreting various adipocytokines. Plasma visfatin, an adipocytokine predominantly secreted from visceral adipose tissue, has insulin-mimetic effects, and has been closely linked to insulin resistance.Objective To compare plasma visfatin levels between obese and non-obese adolescents, as well as between obese adolecents with and without insulin resistance.Methods This cross-sectional study was conducted in students who attended three senior high schools in Padang. Subjects comprised 28 obese and 28 non-obese adolescents. The age of the subjects ranged from 14-18 years. Obesity criteria were based on body mass index (BMI) measurements. Fasting serum glucose level was measured by glucose hexokinase photometry and serum insulin was measured by chemiluminesence immunoassay. Plasma visfatin was measured by enzyme-linked immunosorbent assay (ELISA). The insulin resistance index was estimated from fasting serum insulin and glucose levels using the homeostatic model assessment for insulin resistance (HOMA-IR). Differences in the variables were tested using independent T-test and Mann-Whitney test, depending on the distribution of the variables.Results The mean plasma visfatin level was significantly higher in the obese than in the control group [2.55 (SD 1.54) vs. 1.61 (SD 0.64) ng/mL, respectively; (P=0.005)]. The insulin resistant group had significantly higher mean plasma visfatin level than the non-resistant group [3.61 (SD 1.59) vs. 1.96 (SD 1.18) ng/mL, respectively; (P=0.004)].Conclusion Obese adolescents with insulin resistance have signifcantly higher plasma visfatin levels compared to those without insulin resistance.

scholarly journals Serum levels of the myokine irisin in relation to metabolic and renal function

2014 ◽  
Vol 170 (4) ◽  
pp. 501-506 ◽  
Author(s):  
Thomas Ebert ◽  
Denise Focke ◽  
David Petroff ◽  
Ulrike Wurst ◽  
Judit Richter ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Renal Function ◽  
Univariate Analysis ◽  
Visceral Obesity ◽  
Serum Levels ◽  
Model Assessment ◽  
Glucose And Lipid Metabolism ◽  
The Metabolic Syndrome ◽  
Physiological Relevance ◽  
Ckd Stage

ObjectiveIrisin has recently been introduced as a novel myokine which reverses visceral obesity and improves glucose metabolism in mice. However, regulation of irisin in humans in relation to renal and metabolic disease has not been comprehensively studied.Design and methodsSerum irisin levels were quantified by ELISA and correlated with anthropometric and biochemical parameters of renal function, glucose and lipid metabolism, as well as inflammation, in 532 patients with stages 1–5 of chronic kidney disease (CKD).ResultsMedian serum irisin levels adjusted for age, gender, and BMI significantly decreased with increasing CKD stage and lowest concentrations were seen in patients with CKD stage 5. Furthermore, irisin concentrations were associated with facets of the metabolic syndrome including diastolic blood pressure, markers of impaired glucose tolerance, and dyslipidemia in univariate analysis. Moreover, markers of renal function, e.g. glomerular filtration rate, and insulin resistance, e.g. homeostasis model assessment of insulin resistance, remained independently associated with circulating irisin levels in robust multivariate analysis.ConclusionsWe show that irisin serum concentrations decrease with increasing CKD stage and are independently and positively predicted by renal function and insulin resistance. The physiological relevance of our findings, as well as the factors contributing to irisin regulation in humans, needs to be further defined in future experiments.

Targeted inhibition of CD74 attenuates adipose COX-2-MIF-mediated M1 macrophage polarization and retards obesity-related adipose tissue inflammation and insulin resistance

2018 ◽  
Vol 132 (14) ◽  
pp. 1581-1596 ◽  
Author(s):  
Pei-Chi Chan ◽  
Ting-Ni Wu ◽  
Ying-Chuan Chen ◽  
Chieh-Hua Lu ◽  
Martin Wabitsch ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Mrna Levels ◽  
Model Assessment ◽  
M1 Macrophage ◽  
Cox 2 ◽  
Highly Correlated ◽  
Targeted Inhibition

Adipose tissue (AT) inflammation is crucial to the development of obesity-associated insulin resistance. Our aim was to investigate the contribution of cyclooxygenase-2 (COX-2)/macrophage migration inhibitory factor (MIF)-mediated cross-talk between hypertrophic adipocytes and macrophages to the etiology of AT inflammation and the involvement of CD74 using human SGBS adipocytes, THP-1 macrophages and mice fed a high-fat (HF) diet. The MIF and CD74 mRNA levels in the adipocytes and stromal vascular cells (SVCs) of white fat were highly correlated with body weight (BW), homeostatic model assessment for insulin resistance (HOMA-IR), and adipose macrophage marker expression levels, especially those in SVCs. COX-2 inhibition suppressed the elevation of MIF production in HF white adipocytes as well as palmitate and hypoxic-treated SGBS adipocytes. Treatment of adipocytes transfected with shCOX-2 and siMIF or subjected to MIF depletion in the medium reversed the pro-inflammatory responses in co-incubated THP-1 cells. Inhibition of NF-κB activation reversed the COX2-dependent MIF secretion from treated adipocytes. The targeted inhibition of macrophage CD74 prevented M1 macrophage polarization in the above co-culture model. The COX-2-dependent increases in CD74 gene expression and MIF release in M1-polarized macrophages facilitated the expression of COX-2 and MIF in co-cultured SGBS adipocytes. CD74 shRNA intravenous injection suppressed HF-induced AT M1 macrophage polarization and inflammation as well as insulin resistance in mice. The present study suggested that COX-2-mediated MIF secretion through NF-κB activation from hypertrophic and hypoxic adipocytes as well as M1 macrophages might substantially contribute to the phenotypic switch of AT macrophages through CD74 in obesity. Inhibition of CD74 could attenuate AT inflammation and insulin resistance in the development of HF diet-induced obesity.

scholarly journals Hematopoietic Cell–Expressed Endothelial Nitric Oxide Protects the Liver From Insulin Resistance

2020 ◽  
Vol 40 (3) ◽  
pp. 670-681
Author(s):  
Brian P. Dick ◽  
Ryan McMahan ◽  
Taft Knowles ◽  
Lev Becker ◽  
Sina A. Gharib ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Bone Marrow ◽  
Inflammatory Responses ◽  
Hepatic Insulin Resistance ◽  
Metabolic Homeostasis ◽  
Wild Type ◽  
Bone Marrow Derived Cells ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Objective: Mice genetically deficient in endothelial nitric oxide synthase (Nos3 −/− ) have fasting hyperinsulinemia and hepatic insulin resistance, indicating the importance of Nos3 (nitric oxide synthase) in maintaining metabolic homeostasis. Although the current paradigm holds that these metabolic effects are derived specifically from the expression of Nos3 in the endothelium, it has been established that bone marrow–derived cells also express Nos3. The aim of this study was to investigate whether bone marrow–derived cell Nos3 is important in maintaining metabolic homeostasis. Approach and Results: To test the hypothesis that bone marrow–derived cell Nos3 contributes to metabolic homeostasis, we generated chimeric male mice deficient or competent for Nos3 expression in circulating blood cells. These mice were placed on a low-fat diet for 5 weeks, a time period which is known to induce hepatic insulin resistance in global Nos3-deficient mice but not in wild-type C57Bl/6 mice. Surprisingly, we found that the absence of Nos3 in the bone marrow–derived component is associated with hepatic insulin resistance and that restoration of Nos3 in the bone marrow–derived component in global Nos3-deficient mice is sufficient to restore hepatic insulin sensitivity. Furthermore, we found that overexpression of Nos3 in bone marrow–derived component in wild-type mice attenuates the development of hepatic insulin resistance during high-fat feeding. Finally, compared with wild-type macrophages, the loss of macrophage Nos3 is associated with increased inflammatory responses to lipopolysaccharides and reduced anti-inflammatory responses to IL-4, a macrophage phenotype associated with the development of hepatic and systemic insulin resistance. Conclusions: These results would suggest that the metabolic and hepatic consequences of high-fat feeding are mediated by loss of Nos3/nitric oxide actions in bone marrow–derived cells, not in endothelial cells.

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