Abstract 205: Protective Role for B-1 B Cells and IgM Antibodies in Obesity

Innate B-1 B cells can protect against inflammatory disease through production of natural IgM antibodies, but little is known regarding their role in obesity-induced metabolic dysfunction. In this study, we explore the role murine B-1 B cells play in regulating diet-induced glucose intolerance. In addition, we examine bariatric surgery samples for the presence of B cells in human adipose tissue and circulating natural IgM antibodies. We show that mice with increased visceral adipose tissue B-1b B cells due to B cell specific deletion of Id3 (Id3 BcellKO ) have attenuated high-fat diet-induced glucose intolerance compared to littermate controls. Omental visceral adipose tissue from Id3 BcellKO mice had enhanced local natural IgM antibody secretion (49.0 ± 5.9 vs. 17.5 ± 4.2 U/mg fat), and demonstrated attenuated HFD-induced secretion of TNFa (2.5 ± 0.3 vs. 6.7 ± 1.3 pg/mg fat) and IFNg (0.10 ± 0.02 vs. 0.48 ± 0.14 pg/mg fat). Adoptive transfer of B-1b B cells null for Id3 protected against diet-induced glucose intolerance in Rag1 -/- hosts, while B-1b B cells unable to secrete IgM had no effect. Additional studies in humans undergoing bariatric surgery showed CD20+CD27+CD43+ B cells, previously shown to have B-1-like characteristics, within omental adipose tissue. A correlation was found between their presence and serum natural IgM levels (r=0.52). In addition, natural IgM levels were inversely associated with the inflammatory chemokine, MCP-1 (r=-0.21). Finally, IgM, but not IgG, natural antibodies were inversely associated with insulin resistance (r=0.32). Together, our findings provide the first evidence that B-1b B cells protect against diet-induced glucose intolerance in an IgM-dependent manner in mice, and suggest that anti-inflammatory natural IgM antibodies may modulate the inflammatory and metabolic consequences of obesity in humans.

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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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24 The effect of bariatric surgery on DNA methylation in blood and omental visceral adipose tissue

10.1055/s-0041-1735683 ◽

2021 ◽

Author(s):

Luise Müller ◽

Lena Gras ◽

Anne Hoffmann ◽

Tobias Hagemann ◽

Stephan H. Bernhart ◽

...

Keyword(s):

Bariatric Surgery ◽

Dna Methylation ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

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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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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Human adipose tissue accumulation is connected with pro-inflammatory changes in subcutaneous rather than visceral adipose tissue

Atherosclerosis ◽

10.1016/j.atherosclerosis.2017.06.238 ◽

2017 ◽

Vol 263 ◽

pp. e72

Author(s):

Ivana Kralova Lesna ◽

Anna Kralova ◽

Sona Cejkova ◽

Jiri Fronek ◽

Marek Petras ◽

...

Keyword(s):

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Human Adipose Tissue ◽

Tissue Accumulation ◽

Visceral Adipose ◽

Inflammatory Changes

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VISCERAL ADIPOSE TISSUE INFLUENCES ANTI-TUMOR NECROSIS FACTOR (TNF) TREATMENT RESPONSE IN IBD

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa347.111 ◽

2021 ◽

Vol 27 (Supplement_1) ◽

pp. S46-S47

Author(s):

Phillip Gu ◽

Avneesh Chhabra ◽

Punya Chhittajallu ◽

Christopher Chang ◽

Denisse Mendez ◽

...

Keyword(s):

Adipose Tissue ◽

Treatment Response ◽

Visceral Adipose Tissue ◽

Three Dimensional ◽

Composite Endpoint ◽

Fecal Calprotectin ◽

Dependent Manner ◽

Multicenter Cohort Study ◽

Significant Difference ◽

Visceral Adipose

Abstract Background Data describing the effect of obesity on anti-TNF treatment response in inflammatory bowel disease (IBD) are conflicting. This likely reflects the shortcomings of using body mass index (BMI) to capture an individual’s adipose stores. Recent studies have found visceral adipose tissue (VAT), not BMI, is associated with IBD-related complications and post-operative recurrence. However, the relationship between VAT and treatment response is unclear. We aim to evaluate the effect of VAT on anti-TNF treatment response. Methods IBD patients starting anti-TNF agents between 1/1/2009 to 7/31/2019 at two academic medical centers were included. Three-dimensional VAT volume was measured from CT scans with Aquarius (iNtuition, Foster City, CA). Patients were categorized by predefined volume cutoffs: <1500cm3, 1500-2999cm3, >3000cm3. Primary outcomes included composite endpoint of corticosteroid-free response (CFR) at 6 and 12 months defined by meeting one of the following: a) clinical response based on Harvey Bradshaw Index for Crohn’s disease (CD) or Lichtiger score for ulcerative colitis (UC) b) endoscopic improvement based on ulcer healing for CD and Mayo score for UC compared to baseline or c) 50% improvement or normalization of CRP or fecal calprotectin. Secondary outcomes included IBD-related surgery at 6 and 12 months. We performed a multivariable logistic regression on CFR and surgery, adjusting for age, gender, IBD diagnosis, disease duration, active tobacco use, and immunomodulator exposure, to calculate adjusted odds ratio (aOR) and 95% confidence interval (CI). Results We included 182 patients. Table 1 summarizes differences in baseline characteristics. There were no differences in CFR at 6 months. Compared to those with VAT volume <1500cm3, patients with VAT volume 1500-2999cm3 were significantly more likely to achieve CFR at 12 months (aOR 3.27, [95%CI 1.26–8.5]), but not for those with VAT volume >3000cm3 (aOR 0.45, [95%CI 0.13–1.50], Figure 1b). With respect to surgery within 6 months, patients with volume >3000cm3 were significantly more likely to undergo surgery than those with VAT volume <1500cm3 (aOR: 7.99 [95%CI 1.49–2.94]), while there was no significant difference with patients with VAT volume 1500-2999cm3 (aOR: 0.63 [95%CI 0.14–2.78]). While not statistically significant, a similar trend was observed at 12 months with those with VAT volume >3000cm3 having the highest risk of surgery (aOR: 3.55 [95%CI 0.87–14.61], Figure 1c and d). Conclusion In this retrospective, multicenter, cohort study, we found VAT influences treatment response but not in a dose-dependent manner as previously hypothesized. If confirmed by future prospective studies, VAT may be employed as a biomarker to better inform treatment decisions and improve outcomes, especially considering the growth of artificial intelligence in medical imaging.

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Changes in Visceral Fat and Its Correlation With Changes in Metabolic Variables After Bariatric Surgery

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.012 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A6-A7

Author(s):

Eduardo Doval ◽

Susana Reyes Lopez ◽

Alejandra Albarran ◽

Ernesto Sosa ◽

Claudia Ramirez ◽

...

Keyword(s):

Bariatric Surgery ◽

Gastric Bypass ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Fasting Glucose ◽

Metabolic Markers ◽

Average Decrease ◽

Metabolic Variables ◽

Visceral Adipose ◽

Hba1c Levels

Abstract Obesity is a health problem. There is a relationship between visceral adipose tissue (VAT) and various metabolic components. So far the most effective treatment for weight reduction and control of comorbidities is bariatric surgery. After bariatric surgery there is a reduction in VAT and a correlation with better control of metabolic variables would be expected. Objective: To determine the decrease in VAT, calculated by bioimpedance at 3 and 6 months after bariatric surgery and its correlation with changes in metabolic parameters (fasting glucose, HOMA, HbA1c, lipid profile). MATERIAL AND Methods: Patients belonging to the HECMNSXXI Obesity Clinic undergoing bariatric surgery during 2020 who agreed to participate in the study were included. VAT volume was determined before surgery and at 3 and 6 months after the procedure by bioimpedance using the SECA mBCA525 body analyzer. At the same time, biochemical metabolic markers were determined (fasting glucose, HOMA, HbA1c, CT, HDL, LDL, and triglycerides). The results were reported using descriptive statistics. A Pearson or Spearman correlation was carried out according to the distribution of the variables. P <0.05 was taken as significant. Results: Eleven patients with a mean age of 49 ± 7 years were included, 73% of them were women. Their average initial BMI was 42 ± 4 kg/m2. VAT prior to surgery had a mean of 10.6 ± 2.5L for men and 6.4 ± 2.4L for women. Eighty-two percent of the patients fulfilled harmonized criteria for metabolic syndrome. There was a statistically significant decrease in VAT at 3 and 6 months after surgery in both men and women (Baseline 7.5 ± 3L, 3 months 3.8 ± 2.8 L (p <0.001), 6 months 2.5 ± 2 L (p = 0.001). An average decrease in visceral adipose tissue of 57 ± 24% in women and 34 ± 18% in men (p = 0.18) was found 3 months after surgery and 70 ± 22% in women and 60 ± 21% in men (p = 0.53) 6 months after surgery. Laparoscopic one-anastomosis gastric bypass (OAGB) was the type of surgery with the highest percentage of VAT loss at 3 and 6 months, however, this was not statistically significant when compared with Y-Roux Gastric bypass (YRGB). A statistically significant decrease in HbA1c, HOMA, total cholesterol, LDL, and triglycerides levels were found at 3 and 6 months after surgery. However, when correlating the proportion of VAT lost with the metabolic variables, only a significant correlation was found with the HbA1c levels. The higher the proportion of VAT lost, the lower the HbA1c levels (R2 -0.72 p = 0.01). Conclusions: Bariatric surgery produces a statistically significant reduction in visceral adipose tissue from 3 months after surgery. In this study, an inversely proportional correlation was found between the proportion of VAT lost and HbA1c levels.

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Abstract 3592: Early Detection Of CD4-positive Lymphocytes In Adipose Tissue During The Development Of Insulin Resistance

Circulation ◽

10.1161/circ.116.suppl_16.ii_813-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Katharina Hess ◽

Nikolaus Marx ◽

Martin Wabitsch ◽

Thomas Skurk ◽

Hans Hauner ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Immunohistochemical Staining ◽

Human Adipose Tissue ◽

Adipose Tissue Inflammation ◽

Rt Pcr ◽

Tissue Inflammation ◽

Visceral Adipose

Background: Adipose tissue inflammation may play a critical role in the pathogenesis of insulin resistance (IR) and arteriosclerosis. Previous work has mainly focused on the role of macrophages in human adipose tissue, but little is known about pro-inflammatory T-lymphocytes. Therefore the present study examined the role of CD4-positive lymphocytes in adipose tissue inflammation and IR. Results: Both, CD4-positive lymphocytes and macrophages are present in human visceral adipose tissue as determined by immunohistochemical staining. Most macrophages were HLA-DR positive, reflecting activation through IFNγ, a cytokine released from CD4-positive lymphocytes. Furthermore, SDF-1α, a T-cell chemotactic protein, was also detectable in human adipose tissue. RT-PCR analyses confirmed the expression of IFNγ and SDF1α in visceral adipose tissue. Freshly isolated human adipocytes as well SGBS adipocyte cells express SDF-1α with a down regulation of its expression during adipocyte differentiation in both cell types. In a mouse model of IR, high fat diet induced IR already after 5 weeks which was associated with a marked lymphocyte infiltration in visceral adipose tissue as determined by immunohistochemical staining and RT-PCR. In contrast, macrophages were absent after 5 weeks of diet but could be detected at week 10, suggesting early infiltration of lymphocytes during the development of IR. Conclusion: Pro-inflammatory T-lymphocytes are present in visceral adipose tissue and may contribute to local inflammatory cell activation before the appearance of macrophages. These data suggest that lymphocytes may play an important role in the initiation and perpetuation of adipose tissue inflammation as well as the development of insulin resistance.

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Visceral Adipose Tissue Volumetrics Inform Odds of Treatment Response and Risk of Subsequent Surgery in IBD Patients Starting Antitumor Necrosis Factor Therapy

Inflammatory Bowel Diseases ◽

10.1093/ibd/izab167 ◽

2021 ◽

Author(s):

Phillip Gu ◽

Avneesh Chhabra ◽

Punya Chittajallu ◽

Christopher Chang ◽

Denisse Mendez ◽

...

Keyword(s):

Adipose Tissue ◽

Treatment Response ◽

Visceral Adipose Tissue ◽

Dependent Manner ◽

3 Dimensional ◽

Dimensional Measurements ◽

Factor Therapy ◽

Post Hoc ◽

Visceral Adipose ◽

Necrosis Factor

Abstract Background Data describing the effect of obesity on antitumor necrosis factor (anti-TNF) treatment response are inconsistent. Visceral adipose tissue (VAT) is a superior marker of adiposity to body mass index. However, its effect on treatment response is unclear. We aimed to evaluate the effect of VAT on anti-TNF treatment response. Methods Inflammatory bowel disease (IBD) patients starting anti-TNF agents between January 1, 2009, and July 31, 2019, were included. 3-dimensional measurements of VAT volume and visceral fat index (visceral:subcutaneous adipose tissue ratio; VFI) were obtained from computed tomography (CT) scans. Subjects were categorized by predefined volume cutoffs (<1500cm3, 1500–2999cm3, ≥3000cm3) and VFI (<0.33, 0.33–0.66, ≥0.67). Primary outcomes included a composite treatment response end point at 6 and 12 months. Secondary outcomes were surgery at 6 and 12 months. Multivariable logistic regression was used to calculate adjusted odds ratio (aOR) and 95% confidence interval (CI). Results The final cohort included 176 patients. No significant differences in treatment response at 6 months was observed. At 12 months, compared with volume <1500cm3, patients with volume 1500–2999cm3 had higher odds of response (aOR, 3.52; 95% CI, 1.16–10.71; P = .023), whereas volume ≥3000cm3 did not. Compared with VFI<0.33, VFI ≥0.67 had higher odds of surgery at 6 (aOR, 48.22; 95% CI, 4.73–491.57; P = .023) and 12 months (aOR, 20.94; 95% CI, 3.14–139.67; P = .004). Post hoc analysis suggested VAT may affect drug pharmacokinetics. Conclusions We found VAT volume is associated with anti-TNF treatment response in a nondose dependent manner, and VFI may inform risk of surgery after anti-TNF initiation. If confirmed by prospective studies, VAT volumetrics are potentially useful biomarkers to inform IBD treatment decisions.

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