The Gene Expression of the Main Lipogenic Enzymes is Downregulated in Visceral Adipose Tissue of Obese Subjects

Abstract Obesity and body fat distribution are important risk factors for the development of type 2 diabetes and metabolic syndrome. Evidence has accumulated that this risk is related to intrinsic differences in behavior of adipocytes in different fat depots. We recently identified LIM domain only 3 (LMO3) in human mature visceral adipocytes; however, its function in these cells is currently unknown. The aim of this study was to determine the potential involvement of LMO3-dependent pathways in the modulation of key functions of mature adipocytes during obesity. Based on a recently engineered hybrid rAAV serotype Rec2 shown to efficiently transduce both brown adipose tissue (BAT) and white adipose tissue (WAT), we delivered YFP or Lmo3 to epididymal WAT (eWAT) of C57Bl6/J mice on a high-fat diet (HFD). The effects of eWAT transduction on metabolic parameters were evaluated 10 weeks later. To further define the role of LMO3 in insulin-stimulated glucose uptake, insulin signaling, adipocyte bioenergetics, as well as endocrine function, experiments were conducted in 3T3-L1 adipocytes and newly differentiated human primary mature adipocytes, engineered for transient gain or loss of LMO3 expression, respectively. AAV transduction of eWAT results in strong and stable Lmo3 expression specifically in the adipocyte fraction over a course of 10 weeks with HFD feeding. LMO3 expression in eWAT significantly improved insulin sensitivity and healthy visceral adipose tissue expansion in diet-induced obesity, paralleled by increased serum adiponectin. In vitro, LMO3 expression in 3T3-L1 adipocytes increased PPARγ transcriptional activity, insulin-stimulated GLUT4 translocation and glucose uptake, as well as mitochondrial oxidative capacity in addition to fatty acid oxidation. Mechanistically, LMO3 induced the PPARγ coregulator Ncoa1, which was required for LMO3 to enhance glucose uptake and mitochondrial oxidative gene expression. In human mature adipocytes, LMO3 overexpression promoted, while silencing of LMO3 suppressed mitochondrial oxidative capacity. LMO3 expression in visceral adipose tissue regulates multiple genes that preserve adipose tissue functionality during obesity, such as glucose metabolism, insulin sensitivity, mitochondrial function, and adiponectin secretion. Together with increased PPARγ activity and Ncoa1 expression, these gene expression changes promote insulin-induced GLUT4 translocation, glucose uptake in addition to increased mitochondrial oxidative capacity, limiting HFD-induced adipose dysfunction. These data add LMO3 as a novel regulator improving visceral adipose tissue function during obesity. Key messages LMO3 increases beneficial visceral adipose tissue expansion and insulin sensitivity in vivo. LMO3 increases glucose uptake and oxidative mitochondrial activity in adipocytes. LMO3 increases nuclear coactivator 1 (Ncoa1). LMO3-enhanced glucose uptake and mitochondrial gene expression requires Ncoa1.

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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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Free-amino acid metabolic profiling of visceral adipose tissue from obese subjects

Amino Acids ◽

10.1007/s00726-020-02877-6 ◽

2020 ◽

Vol 52 (8) ◽

pp. 1125-1137

Author(s):

M. C. Piro ◽

M. Tesauro ◽

A. M. Lena ◽

P. Gentileschi ◽

G. Sica ◽

...

Keyword(s):

Adipose Tissue ◽

Amino Acid ◽

Free Amino Acid ◽

Visceral Adipose Tissue ◽

Metabolic Profiling ◽

Free Amino ◽

Obese Subjects ◽

Visceral Adipose

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Abstract 17843: Visceral Adipose Tissue Secretion of Adiponectin Decreases with Increased Body Mass Index

Circulation ◽

10.1161/circ.130.suppl_2.17843 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Lenore R Rengel ◽

Brittaney Obi ◽

Jon Gould ◽

Matthew Goldblatt ◽

Andrew Kastenmeier ◽

...

Keyword(s):

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Metabolic Health ◽

Metabolically Healthy Obese ◽

Obese Subjects ◽

Healthy Obese ◽

Metabolically Healthy ◽

Visceral Adipose ◽

Subcutaneous Adipose

Introduction: Peripheral adiposity is associated with better metabolic health and higher plasma adiponectin (ADPN) levels. Since ADPN is secreted mainly by adipose tissue (AT), it is intriguing that higher visceral adipose tissue (VAT) is associated with lower ADPN levels and poor metabolic health. Hypothesis: We hypothesized that various AT depots differ in their ability to secrete ADPN. Methods: Paired AT samples (VAT and subcutaneous adipose tissue (SAT)) were collected from 19 subjects (10 women, 15 obese) undergoing elective abdominal surgery. The samples were cultured and the supernatant was collected after 24 hours. ADPN levels released into the supernatant from VAT and SAT were measured using multiplex methods. Subjects were defined as obese or non-obese (NO) based on BMI > or ≤ 30kg/m2 respectively. Obese subjects were further classified as metabolically unhealthy obese (MUO) or metabolically healthy obese (MHO) based on presence or absence of type 2 diabetes mellitus, hypertension, or cardiovascular disease at the time of surgery. Results: Mean ADPN secretion levels from SAT and VAT were similar in NO subjects (17.3 ± 3.4 vs. 9.8 ± 13.0 ng/mL/mg, p=0.5) whereas the mean ADPN secretion was lower from VAT among obese subjects (15.9 ± 0.8 vs. 4.5 ± 0.2 ng/mL/mg, p=0.0002). ADPN secretion decreased from VAT (r=-0.16) and increased from SAT (r=0.33) with increased BMI (Fig.1). When MHO and MUO were compared, ADPN secretion from VAT in MHO was reduced only slightly (16.1 ± 8.2 vs. 4.0 ± 2.0 ng/mL/mg, p=0.07) whereas ADPN secretion was significantly reduced in MUO (15.9 ± 5.3 vs. 4.7 ± 4.6 ng/mL/mg, p=0.003). Conclusions: Reduced ADPN secretion from VAT in subjects with increasing BMI may explain lower circulating ADPN levels in obese individuals. Higher ADPN production from SAT and the relatively preserved secretion of ADPN from VAT may explain metabolic health in some obese individuals. Futures studies will help identify factors that control ADPN secretion from AT.

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Regional Variation in Plasminogen Activator Inhibitor-1 Expression in Adipose Tissue from Obese Individuals

Thrombosis and Haemostasis ◽

10.1055/s-0037-1613860 ◽

2000 ◽

Vol 83 (04) ◽

pp. 545-548 ◽

Cited By ~ 76

Author(s):

Vanessa Van Harmelen ◽

Johan Hoffstedt ◽

Per Lundquist ◽

Hubert Vidal ◽

Veronika Stemme ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Subcutaneous Adipose Tissue ◽

Plasminogen Activator Inhibitor ◽

Plasminogen Activator Inhibitor 1 ◽

Visceral Adipose ◽

Subcutaneous Adipose ◽

Activator Inhibitor ◽

Pai 1

SummaryHigh plasma plasminogen activator inhibitor-1 (PAI-1) activity is a frequent finding in obesity and adipose tissue has recently been suggested to be a source of circulating PAI-1 in humans. In the present study, differences in adipose tissue gene expression and protein secretion rate of PAI-1 between subcutaneous and visceral adipose tissue was analysed in specimens obtained from 22 obese individuals. The secretion rate of PAI-1 was two-fold higher in subcutaneous adipose tissue than in visceral adipose tissue (292 ± 50 vs 138 ± 24 ng PAI-1/107 cells, P <0.05). In accordance with the secretion data, subcutaneous adipose tissue contained about three-fold higher levels of PAI-1 mRNA than visceral adipose tissue (2.43 ± 0.37 vs 0.81 ± 0.12 attomole PAI-1 mRNA/µg total RNA, P <0.001). PAI-1 secretion from subcutaneous but not from visceral adipose tissue correlated significantly with cell size (r = 0.43, P <0.05). In summary, subcutaneous adipose tissue secreted greater amounts of PAI-1 and had a higher PAI-1 gene expression than visceral adipose tissue from the same obese individuals. Bearing in mind that subcutaneous adipose tissue is the largest fat depot these finding may be important for the coagulation abnormalities associated with obesity.

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Inverse relationship between obesity and FTO gene expression in visceral adipose tissue in humans

Diabetologia ◽

10.1007/s00125-008-0928-9 ◽

2008 ◽

Vol 51 (4) ◽

pp. 641-647 ◽

Cited By ~ 62

Author(s):

N. Klöting ◽

D. Schleinitz ◽

K. Ruschke ◽

J. Berndt ◽

M. Fasshauer ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Inverse Relationship ◽

Fto Gene ◽

Visceral Adipose

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Epigenetic Downregulation of FASN in Visceral Adipose Tissue of Insulin Resistant Subjects

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-1150-7446 ◽

2020 ◽

Author(s):

Helen Sievert ◽

Christin Krause ◽

Cathleen Geißler ◽

Martina Grohs ◽

Alexander T. El-Gammal ◽

...

Keyword(s):

Type 2 Diabetes ◽

Dna Methylation ◽

Fatty Acids ◽

Adipose Tissue ◽

Glucose Intolerance ◽

Visceral Adipose Tissue ◽

High Hba1c ◽

Obese Subjects ◽

Visceral Adipose

Abstract Objective The risk to develop type 2 diabetes increases with the amount of visceral adiposity presumably due to increased lipolysis and subsequent lipid accumulation in visceral organs. However, data describing the molecular regulation of these pathways in humans are rare. We tested if genes of the lipogenic and lipolytic pathways are associated with glucose intolerance independently of obesity in visceral adipose tissue (VAT) of obese subjects. Moreover, we studied DNA methylation of FASN (fatty acid synthase), that catalyses the synthesis of long-chain fatty acids, in VAT of the same subjects and whether it is associated with metabolic traits. Subjects and methods Visceral adipose tissue biopsies and blood samples were taken from 93 severely obese subjects undergoing bariatric surgery. Subjects were grouped in low HbA1c (L-HbA1c, HbA1c<6.5 %) and high HbA1c (H-HbA1c, HbA1c≥6.5 %) groups and expression of genes from the lipogenic and lipolytic pathways was analysed by TaqMan qPCR. DNA methylation of FASN was quantified by bisulfite-pyrosequencing. Results FASN expression was downregulated in visceral fat from subjects with high HbA1c (p = 0.00009). Expression of other lipogenetic (SCD, ELOVL6) or lipolytic genes (ADRB3, PNPLA2) and FABP4 was not changed. DNA methylation of FASN was increased at a regulatory ChoRE recognition site in the H-HbA1c-subgroup and correlated negatively with FASN mRNA (r = − 0.302, p = 0.0034) and positively with HbA1c (r = 0.296, p = 0.0040) and blood glucose (r = 0.363, p = 0.0005). Conclusions Epigenetic downregulation of FASN in visceral adipose tissue of obese subjects might contribute to limited de novo lipogenesis of important insulin sensitizing fatty acids and could thereby contribute to glucose intolerance and the development of type 2 diabetes independently of obesity.

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Reduced Biliverdin Reductase-A Expression in Visceral Adipose Tissue is Associated with Adipocyte Dysfunction and NAFLD in Human Obesity

International Journal of Molecular Sciences ◽

10.3390/ijms21239091 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9091

Author(s):

Valentina Ceccarelli ◽

Ilaria Barchetta ◽

Flavia Agata Cimini ◽

Laura Bertoccini ◽

Caterina Chiappetta ◽

...

Keyword(s):

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Insulin Signalling ◽

Mrna Levels ◽

Gamma Glutamyl Transpeptidase ◽

Alcoholic Fatty Liver ◽

Biliverdin Reductase ◽

Omental Adipose Tissue ◽

Obese Subjects ◽

Visceral Adipose

Biliverdin reductase A (BVR-A) is an enzyme involved in the regulation of insulin signalling. Knockout (KO) mice for hepatic BVR-A, on a high-fat diet, develop more severe glucose impairment and hepato-steatosis than the wild type, whereas loss of adipocyte BVR-A is associated with increased visceral adipose tissue (VAT) inflammation and adipocyte size. However, BVR-A expression in human VAT has not been investigated. We evaluated BVR-A mRNA expression levels by real-time PCR in the intra-operative omental biopsy of 38 obese subjects and investigated the association with metabolic impairment, VAT dysfunction, and biopsy-proven non-alcoholic fatty liver disease (NAFLD). Individuals with lower VAT BVR-A mRNA levels had significantly greater VAT IL-8 and Caspase 3 expression than those with higher BVR-A. Lower VAT BVR-A mRNA levels were associated with an increased adipocytes’ size. An association between lower VAT BVR-A expression and higher plasma gamma-glutamyl transpeptidase was also observed. Reduced VAT BVR-A was associated with NAFLD with an odds ratio of 1.38 (95% confidence interval: 1.02–1.9; χ2 test) and with AUROC = 0.89 (p = 0.002, 95% CI = 0.76–1.0). In conclusion, reduced BVR-A expression in omental adipose tissue is associated with VAT dysfunction and NAFLD, suggesting a possible involvement of BVR-A in the regulation of VAT homeostasis in presence of obesity.

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Progranulin serum levels and gene expression in subcutaneous vs visceral adipose tissue of severely obese patients undergoing bariatric surgery

Clinical Endocrinology ◽

10.1111/cen.14040 ◽

2019 ◽

Vol 91 (3) ◽

pp. 400-410 ◽

Cited By ~ 3

Author(s):

Judith Brock ◽

Andreas Schmid ◽

Thomas Karrasch ◽

Petra Pfefferle ◽

Jutta Schlegel ◽

...

Keyword(s):

Gene Expression ◽

Bariatric Surgery ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Serum Levels ◽

Obese Patients ◽

Severely Obese ◽

Visceral Adipose

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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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