Study of lactoferrin gene expression in human and mouse adipose tissue, human preadipocytes and mouse 3T3-L1 fibroblasts. Association with adipogenic and inflammatory markers

Abstract Background Non-alcoholic fatty liver disease (NAFLD) includes simple steatosis (SS) and nonalcoholic steatohepatitis (NASH). It affects 74–98% of individuals with morbid obesity undergoing bariatric surgery (BSX). Among several factors contributing to NAFLD pathogenesis, adipokines secreted by visceral adipose tissue (VAT) can play a role by regulating glucose/lipid metabolism and inflammation. Aims This study aims to determine if visceral adipose tissue adipokine and cytokine gene expression are associated with NAFLD (SS and NASH) at the time of BSX. Methods Patients were recruited from the Toronto Western Hospital Bariatric Clinic. Demographic data was recorded. The VAT and liver biopsies were collected at the time of bariatric surgery. VAT adipokines and other mediators were assessed by RT-PCR and included markers of thermogenic capacity, inflammation, fibrosis, adipokines, and others. Liver histology was assessed by a pathologist using the Brunt system and individuals were diagnosed as either SS, NASH, or having a healthy liver (HL). Blood samples were collected pre-BSX to measure liver and metabolic syndrome related parameters, including HOMA-IR, HbA1c, liver enzymes, and lipid profile. Anthropometry was also assessed. Groups were compared using Kruskal-Wallis test followed by Wilcoxon ranked sum, or chi-square and Fisher’s exact test as necessary. Data was considered to be statistically significant with a p-value less than 0.05. Results We are presenting data on 126 patients, 80.2% females with a median age of 49 and a body mass index (BMI) of 46.9. Fifty-seven patients had SS, 34 had NASH and 35 had a healthy liver (HL). BMI, age, and sex did not differ between the three groups. First, we found that those with NASH had significantly higher VAT expression of fibrosis (Loxl2), inflammation (CCL4 and TGFb1) and proliferation markers (E2F1) and significantly lower expression of adipokines (TNFa and resistin) compared to HL. Also, we found that SS had significantly higher fibrosis (Col3a1, Col6a1, Loxl2, CD9 and Acta2), inflammation (Nox2, TGFb1, IFNg and Clec10a), browning (PPARa, PPARg and Glut1) and proliferation (E2F1) marker expression compared to HL. Conclusions Results show that there is a significant difference in the expression pattern of VAT fibrotic and inflammatory markers between HL, SS and NASH patients. The observed increase of inflammatory markers in NAFLD is in line with prior research outlining the ability of inflammatory mediators from VAT to contribute to liver pathology via portal circulation. The relationship between VAT characteristics and NAFLD are important in understanding the widespread metabolic effects of obesity. Funding Agencies CIHRCanadian Liver foundation

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Effect of fructose intake during gestation alters gene expression of obesity and inflammatory markers in adipose tissue

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.733.7 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Nikhil Patel ◽

Chris Lineker ◽

Abha Dunichand‐Hoedl ◽

Michael Symonds ◽

Helen Budge ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Inflammatory Markers ◽

Fructose Intake

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Effect of early-to-mid gestational maternal nutrient restriction followed by adolescent-onset obesity on the gene expression of inflammatory markers in pericardial adipose tissue

Proceedings of The Nutrition Society ◽

10.1017/s0029665109990346 ◽

2009 ◽

Vol 68 (OCE2) ◽

Author(s):

N. Patel ◽

S. Sebert ◽

D. S. Gardner ◽

R. Bell ◽

H. Budge ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Inflammatory Markers ◽

Nutrient Restriction ◽

Pericardial Adipose Tissue

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Effects of Berries on High-Fat Diet-Induced Inflammation

Current Developments in Nutrition ◽

10.1093/cdn/nzaa045_082 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 449-449

Author(s):

Patricia Perez ◽

Desiree Wanders ◽

Hannah Land ◽

Kathryn Chiang ◽

Rami Najjar ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Inflammatory Markers ◽

In Vitro Study ◽

Vitro Study ◽

In Vivo Study ◽

High Fat ◽

Anti Inflammatory

Abstract Objectives Studies suggest that inflammation mediates the link between obesity and its comorbidities including type 2 diabetes and cardiovascular disease. Hence, there is a demand for effective alternative or complementary approaches to treat obesity-associated inflammation. The objective of this study was to determine whether consumption of blackberries (BL) and raspberries (RB) alone or in combination reduce obesity-induced inflammation. Methods In Vitro Study: RAW 264.7 macrophages were pretreated with either BL, RB, or BL + RB, each at a final concentration of 200 µg/mL for 2 h. LPS (1 ng/mL) was then added to the media for 16 h. mRNA expression of inflammatory cytokines was measured. In Vivo Study: Five-week-old mice were acclimated to a low-fat low-sucrose (LFLS) diet for one week after which mice were randomized 10 per group to one of five groups: 1) LFLS, 2) high-fat high-sucrose (HFHS), 3) HFHS + 10% BL, 4) HFHS + 10% RB, or 5) HFHS + 5% BL + 5% RB. Expression of inflammatory markers was measured in the liver as well as epididymal and inguinal white adipose tissue. Results In Vitro Study: Each berry alone and in combination suppressed the LPS-induced increase in inflammatory markers, with the combination (BL + RB) having the greatest effect. The combination suppressed LPS-induced expression of Ccl2, Tnfa, F4/80, and Il6 by 3.7−, 5.3−, 5.3−, and 4.4-fold, respectively. In Vivo Study: Gene expression analysis indicated that berry consumption had no significant effect on proinflammatory (Ccl2, Il1b, Tnfa, Il6, Itgam) or anti-inflammatory (Adipoq, Arg1, Mgl1) markers in adipose tissue depots or liver. However, relatively low gene expression of inflammatory markers in the tissues indicates that the mice fed the HFHS diet failed to develop a robust inflammatory state. Conclusions BL and RB have direct anti-inflammatory effects on immune cells. Initial analysis indicates that consumption of BL and RB has no significant effects on markers of inflammation in a diet-induced mouse model of obesity. However, it is possible that the relatively low levels of inflammation in these mice masked the anti-inflammatory potential of BL and RB. Ongoing analysis will provide additional insights into the effects of BL and RB on inflammation in these tissues. Funding Sources Lewis Foundation Award.

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Adipose Inflammation in Obesity: Relationship With Circulating Levels of Inflammatory Markers and Association With Surgery-Induced Weight Loss

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2013-2673 ◽

2014 ◽

Vol 99 (1) ◽

pp. E53-E61 ◽

Cited By ~ 46

Author(s):

Julie Lasselin ◽

Eric Magne ◽

Cédric Beau ◽

Patrick Ledaguenel ◽

Sandra Dexpert ◽

...

Keyword(s):

Gene Expression ◽

Bariatric Surgery ◽

Weight Loss ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Inflammatory Markers ◽

Tnf Α ◽

Inflammatory State ◽

Adipose Inflammation ◽

Visceral Adipose

Context: The inflammatory state of the adipose tissue is believed to contribute to systemic low-grade inflammation in obesity. Objective: This study assessed the relationship between adipose and circulating inflammatory markers as well as the influence of adipose inflammation on bariatric surgery-induced weight reduction. Design: This was a cross-sectional and longitudinal study (up to 14 mo). Setting: The study was conducted in the digestive/bariatric surgery department of the Tivoli and Jean Villar clinics, Bordeaux, France. Patients: Thirty-seven obese patients [body mass index (BMI) > 35–40 kg/m2)] seeking bariatric surgery were included. Twenty-eight of them were successively followed up at 1–3 months after surgery and 25 between 6 and 14 months after surgery. Main Outcome Measures: Fasting serum samples were collected before surgery to assess concentrations of inflammatory markers. Samples of visceral adipose tissue were extracted during surgery and gene expression of cytokines and immune cell markers were evaluated using quantitative RT-PCR. Pre- and postsurgery weight and BMI were collected. Results: Gene expression of several cytokines were strongly intercorrelated in the visceral adipose tissue. Adipose expression of macrophage and T cell markers were related to adipose expression of TNF-α and IL-1 receptor antagonist (P < .01) and to systemic levels of TNF-α (P < .01) and IL-6 (P < .05). A higher inflammatory state of the adipose tissue predicted a lower BMI reduction after surgery (P < .05), notably at early stages after surgery. Conclusions: These findings support the involvement of macrophages and T cells in adipose inflammation and provide new information regarding the role of the visceral adipose tissue in the inflammatory state of obesity and its impact on obesity treatment outcomes, such as surgery-induced weight loss.

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Adipose tissue gene expression of CXCL10 and CXCL11 modulates inflammatory markers in obesity: implications for metabolic inflammation and insulin resistance

Therapeutic Advances in Endocrinology and Metabolism ◽

10.1177/2042018820930902 ◽

2020 ◽

Vol 11 ◽

pp. 204201882093090

Author(s):

Shihab Kochumon ◽

Ashraf Al Madhoun ◽

Fatema Al-Rashed ◽

Rafaat Azim ◽

Ebaa Al-Ozairi ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Adipose Tissue ◽

Inflammatory Markers ◽

Fasting Blood Glucose ◽

Subcutaneous Fat ◽

Family Members ◽

Enzyme Linked Immunosorbent Assay ◽

Model Assessment ◽

Metabolic Inflammation

Background: The CXCL subfamily of chemokines (CXCL9, CXCL10, and CXCL11; angiostatic chemokines) plays a key role in many inflammatory diseases. However, the expression of CXCLs in adipose tissue (AT) during obesity and association of these CXCLs with inflammatory markers and insulin resistance are poorly understood. Therefore, this study aimed to investigate the effects of CXCL gene expression on subcutaneous AT inflammatory markers and insulin resistance. Methods: Subcutaneous-fat biopsies were collected from 59 nondiabetic (lean/overweight/obese) individuals for RNA isolation. Expression levels of AT CXCL and inflammatory markers were determined by quantitative reverse transcriptase polymerase chain reaction (RT-qPCR). Biomedical parameters in the plasma were measured by enzyme-linked immunosorbent assay (ELISA). Insulin resistance was estimated using homeostatic model assessment (HOMA-IR). Results: AT CXCL expression was higher in obese compared with lean individuals ( p < 0.05) and positively correlated with body mass index (BMI; r ⩾ 0.269, p < 0.05). Expression of CXCL9, CXCL10, and CXCL11 correlated significantly with various pro-inflammatory markers, including family members of interleukins, chemokines, and their prospective receptors ( r ⩾ 0.339, p ⩽ 0.009), but not anti-inflammatory markers. CXCL11 expression correlated specifically with the expression of CCL5, CCL18, TLR3, TLR4, TLR8, IRF5, and NF-κB ( r ⩾ 0.279, p ⩽ 0.039). Notably, CXCL11 was correlated with C-reactive protein (CRP), fasting blood glucose (FBG), and HOMA-IR. In multiple regression analysis, CXCL11 was identified as an independent predictor of CCL19, CCL5, IL-6, and TLR3. Conclusion: These data suggest that the CXCL family members, specifically CXCL10 and CXCL11, are potential biomarkers for the onset of AT inflammation during obesity.

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Autophagy Activity Is Up-Regulated in Adipose Tissue of Obese Individuals and Modulates Proinflammatory Cytokine Expression

Endocrinology ◽

10.1210/en.2012-1625 ◽

2012 ◽

Vol 153 (12) ◽

pp. 5866-5874 ◽

Cited By ~ 115

Author(s):

H. J. Jansen ◽

P. van Essen ◽

T. Koenen ◽

L. A. B. Joosten ◽

M. G. Netea ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Proinflammatory Cytokine ◽

Adipose Tissue Inflammation ◽

Inflammatory Gene Expression ◽

Tissue Inflammation ◽

Inflammatory Gene ◽

Tissue Explants ◽

Autophagy Activity ◽

Human And Mouse

Abstract Autophagy, an evolutionary conserved process aimed at recycling damaged organelles and protein aggregates in the cell, also modulates proinflammatory cytokine production in peripheral blood mononuclear cells. Because adipose tissue inflammation accompanied by elevated levels of proinflammatory cytokines is characteristic for the development of obesity, we hypothesized that modulation of autophagy alters adipose tissue inflammatory gene expression and secretion. We tested our hypothesis using ex vivo and in vivo studies of human and mouse adipose tissue. Levels of the autophagy marker LC3 were elevated in sc adipose tissue of obese vs. lean human subjects and positively correlated to both systemic insulin resistance and morphological characteristics of adipose tissue inflammation. Similarly, autophagic activity levels were increased in adipose tissue of obese and insulin resistant animals as compared with lean mice. Inhibition of autophagy by 3-methylalanine in human and mouse adipose tissue explants led to a significant increase in IL-1β, IL-6, and IL-8 mRNA expression and protein secretion. Noticeably, the enhancement in IL-1β, IL-6, and keratinocyte-derived chemoattractant (KC) by inhibition of autophagy was more robust in the presence of obesity. Similar results were obtained by blocking autophagy using small interfering RNA targeted to ATG7 in human Simpson-Golabi-Behmel syndrome adipocytes. Our results demonstrate that autophagy activity is up-regulated in the adipose tissue of obese individuals and inhibition of autophagy enhances proinflammatory gene expression both in adipocytes and adipose tissue explants. Autophagy may function to dampen inflammatory gene expression and thereby limit excessive inflammation in adipose tissue during obesity.

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