Age and Interleukin-15 Levels Are Independently Associated With Intima-Media Thickness in Obesity-Related NAFLD Patients

Common carotid intima-media thickness (IMT) represents a functional and structural marker of early, precocious, and subclinical atherosclerosis, independently from the carotid plaque. Macrophage cells, which have been detected in adipose tissue and atherosclerotic plaques, are regulated by interleukin-15 (IL-15). At the light of the conflicting results concerning the role of IL-15 in atherosclerosis, the aim of the study was to retrospectively evaluate in a population of 80 obese patients, with median age of 46 years (IQR 34–53 years), with a low rate of comorbidities but with non-alcoholic fatty liver disease (NAFLD) or hepatic steatosis (HS), the relationship between IMT and serum concentrations of IL-15. Anthropometric measures, metabolic profile, and serum inflammatory markers, as well as the levels of IL-15, MCP-1, b FGF, and GM-CSF, were analyzed by a bead-based assay. IMT, HS, subcutaneous, and visceral adipose tissues were detected by ultrasonography. The IL-15 levels of the obese patients were increased with respect to those of 44 young healthy subjects, i.e., 2.77 (1.21–4.8) vs. 1.55 (1–2.4) pg/mL (P = 0.002). In the univariate analysis, IL-15 levels were associated to IMT and to those of MCP-1, b FGF, and GM-CSF, without any relation to other inflammatory markers such as CRP and ferritin, except fibrinogen. In the multivariate analysis, after adjusting the HS severity for the extent of visceral adiposity, a dramatic change in prediction of IMT by HS was shown (β from 0.29 to 0.10, P from 0.008 to 0.37). When the visceral adipose tissue was combined with IL-15, on the one hand, and the well-known coronary artery disease (CAD) risk factors—i.e., age, gender, smoking status, HDL-cholesterol concentrations, triglycerides levels, and HOMA—on the other, only age and IL-15 remained the predictors of IMT (β = 0.60, P = 0.0001 and β = 0.25, P = 0.024, respectively). There was no association of IL-15 with various anthropometric parameters nor with body fat distribution and severity of HS, also after adjusting for age. Age is resulted to be the main factor in the prediction of IMT and thus of early atherosclerosis. The prediction of IMT by IL-15 coupled with the lack of prediction by the well-known CAD risks is in agreement with recent data, which emphasizes the main role of the immune system in the onset/worsening of atherosclerosis, even though the role of visceral adiposity should be further deepened. Age and IL-15 levels were both predictors of early atherosclerosis in this population of obese patients with NAFLD, suggesting a possible role of this cytokine in the atherosclerosis process.

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A214 BARIATRIC SURGERY PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE HAVE DIFFERENT VISCERAL ADIPOSE TISSUE GENE EXPRESSION COMPARED TO THOSE WITH NORMAL LIVER

Journal of the Canadian Association of Gastroenterology ◽

10.1093/jcag/gwab002.212 ◽

2021 ◽

Vol 4 (Supplement_1) ◽

pp. 245-247

Author(s):

S Keshavjee ◽

J Yadav ◽

K Schwenger ◽

S Fischer ◽

T D Jackson ◽

...

Keyword(s):

Gene Expression ◽

Bariatric Surgery ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Inflammatory Markers ◽

Fatty Liver Disease ◽

Alcoholic Fatty Liver ◽

Visceral Adipose ◽

Healthy Liver ◽

Alcoholic Fatty Liver Disease

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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Overexpression of hepatic 5α-reductase and 11β-hydroxysteroid dehydrogenase type 1 in visceral adipose tissue is associated with hyperinsulinemia in morbidly obese patients

Metabolism ◽

10.1016/j.metabol.2011.05.001 ◽

2011 ◽

Vol 60 (12) ◽

pp. 1775-1780 ◽

Cited By ~ 25

Author(s):

René Baudrand ◽

José Miguel Domínguez ◽

Cristian A. Carvajal ◽

Arnoldo Riquelme ◽

Carmen Campino ◽

...

Keyword(s):

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Hydroxysteroid Dehydrogenase ◽

Morbidly Obese ◽

Obese Patients ◽

Visceral Adipose

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Excess of visceral adipose tissue with or without aortic elongation leads to a steeper heart position

Acta Radiologica ◽

10.1177/02841851211034053 ◽

2021 ◽

pp. 028418512110340

Author(s):

S Petteri Kauhanen ◽

Petri Saari ◽

Tarmo Korpela ◽

Timo Liimatainen ◽

Ritva Vanninen ◽

...

Keyword(s):

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Interquartile Range ◽

Obese Patients ◽

Aortic Diseases ◽

Clinical Value ◽

Abdominal Aortic ◽

History Of ◽

Axial Ct ◽

Visceral Adipose

Background The heart’s position determined as the heart–aorta angle (HAA) has been demonstrated to associate with ascending aortic (AA) dilatation. Visceral adipose tissue (VAT) and aortic elongation may shift the heart to the steeper position. Purpose To investigate whether VAT and aortic length influence the HAA. Material and Methods We examined 346 consecutive patients (58.4% men; mean age = 67.0 ± 14.1 years) who underwent aortic computed tomography angiography (CTA). HAA was measured as the angle between the long axis of the heart and AA midline. The amount of VAT was measured at the level of middle L4 vertebra from a single axial CT slice. Aortic length was measured by combining four anatomical segments in different CTA images. The amount of VAT and aortic length were determined as mild with values in the lowest quartile and as excessive with values in the other three quartiles. Results A total of 191 patients (55.2%) had no history of aortic diseases, 134 (38.7%) displayed AA dilatation, 8 (2.3%) had abdominal aortic aneurysm (AAA), and 13 (3.8%) had both AA dilatation and AAA. There was a strong nonlinear regression between smaller HAA and VAT/height, and HAA and aortic length/height. Median HAA was 124.2° (interquartile range 119.0°–130.8°) in patients with a mild amount of VAT versus 120.5° (interquartile range 115.4°–124.7°) in patients with excessive VAT ( P < 0.001). Conclusion An excessive amount of VAT and aortic elongation led to a steeper heart position. These aspects may possess clinical value when evaluating aortic diseases in obese patients.

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The role of visceral adipose tissue on improvement in insulin sensitivity following Roux-en-Y gastric bypass: a study in Chinese diabetic patients with mild and central obesity

Gastroenterology Report ◽

10.1093/gastro/goy024 ◽

2018 ◽

Vol 6 (4) ◽

pp. 298-303 ◽

Cited By ~ 4

Author(s):

Lei Zhao ◽

Liyong Zhu ◽

Zhihong Su ◽

Weizheng Li ◽

Pengzhou Li ◽

...

Keyword(s):

Gastric Bypass ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Visceral Adipose Tissue ◽

Central Obesity ◽

Diabetic Patients ◽

Visceral Adipose

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Protocatechuic acids protects against high glucose- induced insulin resistance in human visceral adipose tissue

Problems of Endocrinology ◽

10.14341/probl201662545-46 ◽

2016 ◽

Vol 62 (5) ◽

pp. 45-46

Author(s):

Paulina Ormazabal ◽

Beatrice Scazzocchio ◽

Rosaria Varì ◽

Annunziata Iacovelli ◽

Roberta Masella

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

High Glucose ◽

Protective Role ◽

Insulin Sensitizer ◽

20 Nm ◽

Visceral Adipose

Adipocytes exposed to high glucose concentrations exhibit impaired insulin signaling. Binding of insulin to its membrane receptor activates insulin metabolic pathway leading to IRS-1 and AKT phosphorylations. The accumulation of visceral adipose tissue (VAT) correlates with insulin resistance and metabolic syndrome. Anthocyanins (ACN) are bioactive food compounds of great nutritional interest. We have shown that protocatechuic acid (PCA), a major metabolite of ACN, might exert insulin-sensitizer activities in human visceral adipose tissue. The aim of this work was to define the protective role of PCA against insulin-resistance induced by high glucose in VAT.Methodology: VAT obtained from control subject (BMI≤25) were separated in four experimental groups: i) PCA: samples treated for 24 h with 100 μM PCA, ii) GLU: VAT treated with 30 mM glucose for 24 h, iii) PCA+GLU: 1 hour incubation with 100 μM PCA before adding glucose (30 mM, 24 h), iv) CTR: vehicle. After treatment, VAT groups were (or not) acutely stimulated with insulin (20 nM, 20 min). Tyr-IRS-1 and Ser-Akt phosphorylations were assessed by Western blotting (WB) in basal or insulin stimulated tissues in all experimental groups. Samples were assessed for IRS-1, IR, Akt and GLUT4 protein content by WB. Results: No differences in protein contents between experimental groups were found. GLU tissues showed a lower increment in insulin-stimulated phosphorylation of IRS-1 and Akt compared to CTR and PCA samples. This impaired activation was completely reversed by the pretreatment with PCA.Conclusion: An in-vitro insulin-resistance condition induced by high glucose was established in biopsies of VAT. PCA restores the ability of GLU-tissues to fully respond to insulin by increasing IRS-1 and Akt phosphorylations. These results confirm the insulin-sensitizer effect of PCA on VAT previously reported by our group. An anthocyanin rich diet might help to protect against insulin-resistance in VAT.

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Osteopontin Expression in Human and Murine Obesity: Extensive Local Up-Regulation in Adipose Tissue but Minimal Systemic Alterations

Endocrinology ◽

10.1210/en.2007-1312 ◽

2007 ◽

Vol 149 (3) ◽

pp. 1350-1357 ◽

Cited By ~ 94

Author(s):

Florian W. Kiefer ◽

Maximilian Zeyda ◽

Jelena Todoric ◽

Joakim Huber ◽

René Geyeregger ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Plasma Concentrations ◽

Morbidly Obese ◽

Low Grade ◽

Obese Patients ◽

Multifunctional Protein ◽

Inflammatory Processes ◽

Low Grade Inflammation

Obesity is associated with a chronic low-grade inflammation characterized by macrophage infiltration of adipose tissue (AT) that may underlie the development of insulin resistance and type 2 diabetes. Osteopontin (OPN) is a multifunctional protein involved in various inflammatory processes, cell migration, and tissue remodeling. Because these processes occur in the AT of obese patients, we studied in detail the regulation of OPN expression in human and murine obesity. The study included 20 morbidly obese patients and 20 age- and sex-matched control subjects, as well as two models (diet-induced and genetic) of murine obesity. In high-fat diet-induced and genetically obese mice, OPN expression was drastically up-regulated in AT (40 and 80-fold, respectively) but remained largely unaltered in liver (<2-fold). Moreover, OPN plasma concentrations remained unchanged in both murine models of obesity, suggesting a particular local but not systemic importance for OPN. OPN expression was strongly elevated also in the AT of obese patients compared with lean subjects in both omental and sc AT. In addition, we detected three OPN isoforms to be expressed in human AT and, strikingly, an obesity induced alteration of the OPN isoform expression pattern. Analysis of AT cellular fractions revealed that OPN is exceptionally highly expressed in AT macrophages in humans and mice. Moreover, OPN expression in AT macrophages was strongly up-regulated by obesity. In conclusion, our data point toward a specific local role of OPN in obese AT. Therefore, OPN could be a critical regulator in obesity induced AT inflammation and insulin resistance.

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Abstract 14315: New Insights Into the Mechanisms of Sepsis: The Role of Proprotein Convertase Subtilisin/kexin Type 9 as a Key Regulator of Pathogen Toxin Clearance

Circulation ◽

10.1161/circ.132.suppl_3.14315 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Elena Topchiy ◽

Yingjin Wang ◽

John Boyd ◽

Keith R Walley

Keyword(s):

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Ex Vivo ◽

Fluorescent Microscopy ◽

Hepatic Uptake ◽

Cardiovascular Complications ◽

Proprotein Convertase ◽

Bacterial Endotoxins ◽

Visceral Adipose

Background: To prevent severe inflammation during infection, the patient must quickly clear bacterial endotoxins from the circulation before they accumulate and are able to interact with immune cells and vascular endothelium, and induce inflammatory organ failure. Bacterial endotoxins are carried within lipoprotein particles. Thus, one mechanism of action for sepsis treatments could be acceleration of lipoprotein clearance by adipocytes and hepatocytes. Proprotein convertase subtilisin/kexin type 9 (PCSK9) decreases the rate of lipoprotein clearance. We have recently reported that reduced function of PCSK9 improves outcome and prevents cardiovascular complications associated with sepsis. Hypothesis: PCSK9 inhibits LDL associated LPS clearance through hepatic LDLR and VLDL associated LPS clearance through adipose VLDLR. Methods and Results: Using siRNA against the LDLR in HepG2 hepatocytes decreased uptake of fluorescently labeled LPS (fLPS) after 48 hours by 1.50±0.10 fold (n=3, p<0.05). Addition of recombinant PCSK9 in the absence of LDLR did not alter uptake of LPS. We confirmed that hepatic uptake of LPS is exclusively via the LDLR by fluorescent microscopy of ex vivo LPS treated primary hepatocytes isolated from LDLR -/- mice. To address the importance of the LDLR upon clearance of LPS from plasma, we injected fLPS into the portal vein of LDLR-/-, PCSK9-/- and wild type mice (WT). Compared to WT, LDLR-/- mice had 36±13% (n=9, p<0.001) increase in plasma LPS after 1 hour, whereas PCSK9-/- show a significant decrease (28±4%, n=9, p<0.001) in plasma LPS. LDLR-/-, but not PCSK9-/- mice showed 46±7% decrease (n=10, p<0.05) in hepatic uptake. On the other hand, compared to the WT PCSK9-/- mice had 200±35% (n=8, p<0.001) increase in LPS uptake by visceral adipose tissue whereas LDLR-/- had no effect compared to WT mice. To further investigate LPS uptake by adipose tissue we injected flLPS into the tail vein of VLDLR-/- and WT mice. VLDLR-/- mice had 33±6% (n=10, p<0.001) decrease in visceral adipose tissue uptake, with no significant change in hepatic uptake. Conclusions: Expression of hepatic LDLR and adipose VLDLR is mainly regulated by PCSK9 and both play important role in clearing LPS from circulation.

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Collagen 24 α1 Is Increased in Insulin-Resistant Skeletal Muscle and Adipose Tissue

International Journal of Molecular Sciences ◽

10.3390/ijms21165738 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5738

Author(s):

Xiong Weng ◽

De Lin ◽

Jeffrey T. J. Huang ◽

Roland H. Stimson ◽

David H. Wasserman ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Insulin Resistant ◽

Global View ◽

Novel Association ◽

Visceral Adipose ◽

Subcutaneous Adipose

Aberrant extracellular matrix (ECM) remodelling in muscle, liver and adipose tissue is a key characteristic of obesity and insulin resistance. Despite its emerging importance, the effective ECM targets remain largely undefined due to limitations of current approaches. Here, we developed a novel ECM-specific mass spectrometry-based proteomics technique to characterise the global view of the ECM changes in the skeletal muscle and liver of mice after high fat (HF) diet feeding. We identified distinct signatures of HF-induced protein changes between skeletal muscle and liver where the ECM remodelling was more prominent in the muscle than liver. In particular, most muscle collagen isoforms were increased by HF diet feeding whereas the liver collagens were differentially but moderately affected highlighting a different role of the ECM remodelling in different tissues of obesity. Moreover, we identified a novel association between collagen 24α1 and insulin resistance in the skeletal muscle. Using quantitative gene expression analysis, we extended this association to the white adipose tissue. Importantly, collagen 24α1 mRNA was increased in the visceral adipose tissue, but not the subcutaneous adipose tissue of obese diabetic subjects compared to lean controls, implying a potential pathogenic role of collagen 24α1 in obesity and type 2 diabetes.

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