Visceral Adipose Tissue Attacks Beyond the Liver: Esophagogastric Junction as a New Target

Abstract

See “Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women,” by Nam SY, Choi IJ, Ryu KH, et al, on page 1902.Given the worldwide increase in rates of obesity, the patient population with obesity-related disorders has risen dramatically. Obesity predisposes individuals to a greater risk of developing several diseases, including atherosclerosis, diabetes mellitus, nonalcoholic fatty liver disease, certain cancers, and immune-mediated disorders. It has been recently recognized that gastroesophageal reflux disease (GERD) including one of its most common manifestations—erosive esophagitis—is also highly associated with obesity.Population-based studies in the last decade have shown convincingly that there exists a strong positive correlation between obesity and GERD symptoms.1El Serag H.B. Petersen N.J. Carter J. et al.Gastroesophageal reflux among different racial groups in the United States.Gastroenterology. 2004; 126: 1692-1699Google Scholar In participants from the Nurses' Health Study, it has been demonstrated that body mass index (BMI) correlates significantly with GERD symptoms.2Jacobson B.C. Somers S.C. Fuchs C.S. et al.Body-mass index and symptoms of gastroesophageal reflux in women.N Engl J Med. 2006; 354: 2340-2348Google Scholar Although it is generally accepted that obesity is associated with erosive esophagitis, correlations of erosive esophagitis with BMI, waist-to-hip ratios, or other measurements of obesity are less clear. However, evidence is increasing that abdominal and not general obesity might be a risk factor for erosive esophagitis, because recent studies have shown that waist circumference as an anthropometric surrogate correlates with erosive esophagitis.3Kang M.S. Park D.I. Oh S.Y. et al.Abdominal obesity is an independent risk factor for erosive esophagitis in a Korean population.J Gastroenterol Hepatol. 2007; 22: 1656-1661Google Scholar A large cross-sectional study of 80,110 individuals suggested also that abdominal diameter rather than BMI was associated with reflux-type symptoms and interestingly this correlation was much more pronounced in the white population and in male subjects.4Corley D.A. Kubo A. Zhao W. Abdominal obesity, ethnicity and gastro-oesophageal reflux symptoms.Gut. 2007; 56: 756-762Google Scholar Furthermore, a recent study demonstrated that visceral adipose tissue as assessed by computed tomography (CT) scan in 750 subjects correlated significantly with the presence of erosive esophagitis.5Chung S.J. Kim D. Park M.J. et al.Metabolic syndrome and visceral obesity as risk factors for reflux oesophagitis: a cross-sectional case-control study of 7078 Koreans undergoing health check-ups.Gut. 2008; 57: 1360-1365Google Scholar In this study, importantly, the metabolic syndrome was associated also with erosive esophagitis, indirectly suggesting that systemic low-grade inflammation as observed in obesity might interact with or even enhance other inflammatory conditions such as esophagitis. Therefore, obesity is associated with a significant higher rate of GERD symptoms, erosive esophagitis, and Barrett's esophagus, as well as esophageal adenocarcinoma.6Hampel H. Abraham N.S. El Serag H.B. Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications.Ann Intern Med. 2005; 143: 199-211Google Scholar, 7Corley D.A. Kubo A. Levin T.R. et al.Abdominal obesity and body mass index as risk factors for Barrett's esophagus.Gastroenterology. 2007; 133: 34-41Google Scholar, 8Edelstein Z.R. Farrow D.C. Bronner M.P. et al.Central adiposity and risk of Barrett's esophagus.Gastroenterology. 2007; 133: 403-411Google Scholar, 9Jacobson B.C. Chan A.T. Giovannucci E.L. et al.Body mass index and Barrett's oesophagus in women.Gut. 2009; 58: 1460-1466Google ScholarIn addition to the established clinical associations between obesity and various diseases, recent research has identified that many of the metabolic/immune phenomena observed in obesity are mediated by a complex network of soluble mediators derived mainly from adipocytes. Adipose tissue is no longer considered to be an inert tissue functioning solely as energy storage, but has evolved as a critical factor in the regulation of many pathologic processes. Various products of the adipose tissue have been characterized and been termed adipocytokines.10Tilg H. Moschen A.R. Adipocytokines: mediators linking adipose tissue, inflammation and immunity.Nat Rev Immunol. 2006; 6: 772-783Google Scholar Adiponectin and leptin are the most abundant adipocytokines produced by adipocytes. Many other products of adipose tissue that have been previously characterized include various proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1, or plasminogen activator inhibitor 1, and several chemokines. Obesity is associated with a chronic inflammatory response characterized by abnormal cytokine production, increased synthesis of acute-phase reactants, such as C-reactive protein, and activation of inflammatory signaling pathways.10Tilg H. Moschen A.R. Adipocytokines: mediators linking adipose tissue, inflammation and immunity.Nat Rev Immunol. 2006; 6: 772-783Google Scholar Although there is no doubt that inflammatory pathways are activated in the visceral and subcutaneous adipose tissue itself in cases of obesity, the total contribution of adipocytes as a source of these circulating and systemically active cytokines, adipocytokines, and chemokines remains unclear. Obese adipose tissue, especially visceral adipose tissue, contains a considerable number of macrophages, making them an additional source of soluble mediators in the adipose tissue. Once macrophages are present and active, together with adipocytes and other cell types present in the adipose tissue, they might perpetuate a vicious cycle of macrophage recruitment and production of inflammatory cytokines.In this issue of Gastroenterology, Nam et al11Nam S.Y. Choi I.J. Ryu K.H. et al.Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women.Gastroenterology. 2010; 139: 1902-1911Google Scholar attempted to answer the critical question of whether abdominal visceral adipose tissue may be associated with presence of erosive esophagitis. In a large prospective study, 5329 participants underwent esophagogastroduodenoscopy and CT scan. Associations between erosive esophagitis and obesity included analysis of adipose visceral tissue, subcutaneous adipose tissue, BMI, waist circumference, and other risk factors. Importantly, the multivariate odds ratio for erosive esophagitis correlated nicely with visceral adipose tissue volume as the odds ratio was almost 3 for >1500 cm3 visceral adipose tissue volume. The 3 measures of obesity—BMI, waist circumference, and visceral adipose—tissue were associated significantly with erosive esophagitis in men, but only visceral adipose tissue showed such a correlation in women, making this parameter the strongest and most robust risk factor. A few other important findings from this large study appeared. (1) There was clear evidence that visceral adipose tissue volume correlated with the severity of esophagitis, suggesting that low-grade inflammation occurring in visceral adipose tissue might influence/enhance extent of inflammation at other locations, that is, distal esophagus. (2) GERD symptoms showed no association with visceral adipose tissue or any other marker of obesity. (3) The prevalence of Barrett's esophagus was 0.7% and did not show any correlation with visceral adipose tissue. (4) Current smoking, male gender, and the presence of hiatal hernia were other risk factors for erosive esophagitis. Strengths of this study are the use of experienced endoscopists involved in this large, prospective study, and the fact that endoscopy and CT scan using a 64-multidetector scan were performed in parallel.Chung et al5Chung S.J. Kim D. Park M.J. et al.Metabolic syndrome and visceral obesity as risk factors for reflux oesophagitis: a cross-sectional case-control study of 7078 Koreans undergoing health check-ups.Gut. 2008; 57: 1360-1365Google Scholar published recently a first cross-sectional study investigating 7078 subjects undergoing upper gastrointestinal endoscopy during a health check-up where they performed assessment of visceral and subcutaneous adipose tissue by CT scan. In this study, and this supports the findings by Nam et al,11Nam S.Y. Choi I.J. Ryu K.H. et al.Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women.Gastroenterology. 2010; 139: 1902-1911Google Scholar again only visceral but not subcutaneous adipose tissue was an independent risk factor for erosive esophagitis after adjusting for other risk factors such as smoking or BMI. In another small study, visceral obesity was quantitated by CT in 100 consecutive patients. These authors also described an association of erosive esophagitis with visceral but not subcutaneous fat.12Lee H.L. Eun C.S. Lee O.Y. et al.Association between erosive esophagitis and visceral fat accumulation quantified by abdominal CT scan.J Clin Gastroenterol. 2009; 43: 240-243Google Scholar Taken together, these studies demonstrate that indeed visceral adipose tissue might play a key role in the pathogenesis of obesity-related erosive esophagitis.Abdominal adiposity may affect the esophagogastric junction mechanically and via metabolic/inflammatory pathways. An obvious and commonly suggested pathogenetic mechanism could be a direct mechanical effect of abdominal obesity leading to an increased intra-abdominal pressure. An increase in BMI and to a lesser extent in waist circumference leads to an increase in acid reflux episodes and longer reflux episodes.13El Serag H.B. Ergun G.A. Pandolfino J. et al.Obesity increases oesophageal acid exposure.Gut. 2007; 56: 749-755Google Scholar Obese patients present with esophagogastric disruption as both BMI and waist circumference correlate with intragastric pressure and increased gastroesophageal pressure gradient.14Pandolfino J.E. El Serag H.B. Zhang Q. et al.Obesity: a challenge to esophagogastric junction integrity.Gastroenterology. 2006; 130: 639-649Abstract Full Text Full Text PDF Scopus (389) Google Scholar Obesity may also affect the lower esophageal sphincter as obesity correlates with an increased transient lower esophageal sphincter relaxation and an increased rate of transient lower esophageal sphincter relaxation with acid reflux.15Wu J.C. Mui L.M. Cheung C.M. et al.Obesity is associated with increased transient lower esophageal sphincter relaxation.Gastroenterology. 2007; 132: 883-889Abstract Full Text Full Text PDF Scopus (243) Google Scholar Nam et al11Nam S.Y. Choi I.J. Ryu K.H. et al.Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women.Gastroenterology. 2010; 139: 1902-1911Google Scholar did not assess intra-abdominal pressure and their excellent correlations between waist circumference and visceral fat suggest that the abdominal cavity may not represent a limited space. Furthermore, an increase in subcutaneous fat would also suggest an enhanced intra-abdominal pressure and there has been no association between subcutaneous fat and erosive esophagitis in both large trials.5Chung S.J. Kim D. Park M.J. et al.Metabolic syndrome and visceral obesity as risk factors for reflux oesophagitis: a cross-sectional case-control study of 7078 Koreans undergoing health check-ups.Gut. 2008; 57: 1360-1365Google Scholar, 11Nam S.Y. Choi I.J. Ryu K.H. et al.Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women.Gastroenterology. 2010; 139: 1902-1911Google Scholar Therefore, it is rather unlikely that simple mechanic aspects play the key role in the association between erosive esophagitis and amount of visceral adipose tissue.In this context, a more attractive interpretation of why visceral adipose tissue might favor development of erosive esophagitis is a “mediator-driven view.” The visceral adipose tissue as stated is a major (adipo)cytokine sink (eg, IL-1, IL-6, TNF-α, leptin, adiponectin, and others) and all these mediators likely exert systemic effects.16You T. Yang R. Lyles M.F. et al.Abdominal adipose tissue cytokine gene expression: relationship to obesity and metabolic risk factors.Am J Physiol Endocrinol Metab. 2005; 288: E741-E747Google Scholar Visceral fat volume directly correlates with serum levels of plasminogen activator inhibitor 1, TNF-α, and IL-6.17Alessi M.C. Bastelica D. Morange P. et al.Plasminogen activator inhibitor 1, transforming growth factor-beta1, and BMI are closely associated in human adipose tissue during morbid obesity.Diabetes. 2000; 49: 1374-1380Google Scholar, 18Bertin E. Nguyen P. Guenounou M. et al.Plasma levels of tumor necrosis factor-alpha (TNF-alpha) are essentially dependent on visceral fat amount in type 2 diabetic patients.Diabetes Metab. 2000; 26: 178-182Google Scholar, 19Park H.S. Park J.Y. Yu R. Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-alpha and IL-6.Diabetes Res Clin Pract. 2005; 69: 29-35Google Scholar Experimental evidence for an important role for this tissue comes from a study where removal of visceral fat in diabetic, obese rats improved insulin resistance and diabetes, clearly suggesting that the visceral adipose tissue maybe critically involved in major aspects of the metabolic syndrome.20Gabriely I. Ma X.H. Yang X.M. et al.Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process?.Diabetes. 2002; 51: 2951-2958Google ScholarVarious (adipo)cytokines derived from the visceral adipose tissue may act systemically, influence and enhance inflammatory processes, and affect both gastric secretion and the esophagogastric junction. The proinflammatory cytokines IL-1 and TNF-α both stimulate gastrin release from human gastric antral fragments.21Beales I.L. Post L. Calam J. et al.Tumour necrosis factor alpha stimulates gastrin release from canine and human antral G cells: possible mechanism of the Helicobacter pylori-gastrin link.Eur J Clin Invest. 1996; 26: 609-611Google Scholar, 22Endo Y. Kumagai K. Induction by interleukin-1, tumor necrosis factor and lipopolysaccharides of histidine decarboxylase in the stomach and prolonged accumulation of gastric acid.Br J Pharmacol. 1998; 125: 842-848Google Scholar Furthermore, neutralization of TNF-α in Crohn's disease patients by a neutralizing antibody (infliximab) decreased gastrin release in response to bombesin.23Hopman W.P. de Jong D.J. Naber A.H. et al.Tumour necrosis factor alpha antibody affects gastrin release in Crohn disease.Scand J Gastroenterol. 2003; 38: 522-525Google Scholar In addition, the distal human esophagus produces cytokines in case of esophagitis and they negatively affect local contractility leading to motor disturbances.24Rieder F. Cheng L. Harnett K.M. et al.Gastroesophageal reflux disease-associated esophagitis induces endogenous cytokine production leading to motor abnormalities.Gastroenterology. 2007; 132: 154-165Google Scholar Direct effects of gastric exposure may be less important, as shown in a recent study by Souza et al,25Souza R.F. Huo X. Mittal V. et al.Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury.Gastroenterology. 2009; 137: 1776-1784Google Scholar who studied the development of esophagitis after esophagoduodenostomy—an animal model of reflux disease. The fact that esophageal inflammation initiates with lymphocyte infiltration in the submucosa not until day 3 and secondarily progresses to the mucosal surface suggests that cytokine-driven mechanisms might be of importance rather than a direct caustic effect owing to gastric acid exposure.The stomach is not only a source of the proinflammatory adipocytokine leptin,26Bado A. Levasseur S. Attoub S. et al.The stomach is a source of leptin.Nature. 1998; 394: 790-793Google Scholar but also a target for leptin; obesity is associated with increased serum leptin levels. Antral mucosa expresses functional leptin receptors and peripheral injection of leptin increased the release of gastrin.27Mix H. Widjaja A. Jandl O. et al.Expression of leptin and leptin receptor isoforms in the human stomach.Gut. 2000; 47: 481-486Google Scholar, 28Goiot H. Attoub S. Kermorgant S. et al.Antral mucosa expresses functional leptin receptors coupled to STAT-3 signaling, which is involved in the control of gastric secretions in the rat.Gastroenterology. 2001; 121: 1417-1427Abstract Full Text Full Text PDF Scopus (49) Google Scholar Serum levels of adiponectin, the potent anti-inflammatory adipocytokine, are decreased in obesity.29Scherer P.E. Williams S. Fogliano M. et al.A novel serum protein similar to C1q, produced exclusively in adipocytes.J Biol Chem. 1995; 270: 26746-26749Google Scholar This adipocytokine is almost exclusively derived from the adipose tissue. Adiponectin effects are mediated via its 2 receptors (types 1 and 2) and it has been shown that stomach and at least esophageal and junctional adenocarcinoma express the type 2 receptor.30Gonzalez C.R. Caminos J.E. Gallego R. et al.Adiponectin receptor 2 is regulated by nutritional status, leptin and pregnancy in a tissue-specific manner.Physiol Behav. 2010; 99: 91-99Google Scholar, 31Howard J.M. Beddy P. Ennis D. et al.Associations between leptin and adiponectin receptor upregulation, visceral obesity and tumour stage in oesophageal and junctional adenocarcinoma.Br J Surg. 2010; 97: 1020-1027Google Scholar Adiponectin circulates in various isoforms and some biological effects are isoform dependent. Whereas high-molecular weight adiponectin has more proinflammatory functions, the low-molecular weight isoform acts more as an anti-inflammatory.32Unger R.H. Scherer P.E. Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity.Trends Endocrinol Metab. 2010; 21: 345-352Google Scholar Importantly, a recent study has found that high levels of low-molecular weight adiponectin are associated with a decreased risk of Barrett's esophagus in patients with GERD,33Rubenstein J.H. Kao J.Y. Madanick R.D. et al.Association of adiponectin multimers with Barrett's esophagus.Gut. 2009; 58: 1583-1589Google Scholar thereby suggesting that a sufficient concentration of the anti-inflammatory adiponectin isoform might prevent inflammation at the esophagogastric junction. The prevalence of Barrett's esophagus is much greater in patients with the metabolic syndrome and associated with increased leptin levels and a trend toward decreased serum adiponectin levels.34Ryan A.M. Healy L.A. Power D.G. et al.Barrett esophagus: prevalence of central adiposity, metabolic syndrome, and a proinflammatory state.Ann Surg. 2008; 247: 909-915Google ScholarAlthough overall information on the interaction of various (adipo)cytokines with stomach, gastric secretion, and the esophagogastric junction is still in its infancy, such a “mediator-driven” concept for the striking correlation of erosive esophagitis with visceral adipose tissue might be attractive. It may well be that various mechanisms are involved in the pathogenesis of obesity-related erosive esophagitis: (1) Mechanical aspects/local injury by pathologic levels of esophageal acid exposure may act as a first hit followed by (2) proinflammatory signals derived from the visceral adipose tissue as a second hit (Figure 1). See “Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women,” by Nam SY, Choi IJ, Ryu KH, et al, on page 1902. See “Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women,” by Nam SY, Choi IJ, Ryu KH, et al, on page 1902. See “Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women,” by Nam SY, Choi IJ, Ryu KH, et al, on page 1902. Given the worldwide increase in rates of obesity, the patient population with obesity-related disorders has risen dramatically. Obesity predisposes individuals to a greater risk of developing several diseases, including atherosclerosis, diabetes mellitus, nonalcoholic fatty liver disease, certain cancers, and immune-mediated disorders. It has been recently recognized that gastroesophageal reflux disease (GERD) including one of its most common manifestations—erosive esophagitis—is also highly associated with obesity. Population-based studies in the last decade have shown convincingly that there exists a strong positive correlation between obesity and GERD symptoms.1El Serag H.B. Petersen N.J. Carter J. et al.Gastroesophageal reflux among different racial groups in the United States.Gastroenterology. 2004; 126: 1692-1699Google Scholar In participants from the Nurses' Health Study, it has been demonstrated that body mass index (BMI) correlates significantly with GERD symptoms.2Jacobson B.C. Somers S.C. Fuchs C.S. et al.Body-mass index and symptoms of gastroesophageal reflux in women.N Engl J Med. 2006; 354: 2340-2348Google Scholar Although it is generally accepted that obesity is associated with erosive esophagitis, correlations of erosive esophagitis with BMI, waist-to-hip ratios, or other measurements of obesity are less clear. However, evidence is increasing that abdominal and not general obesity might be a risk factor for erosive esophagitis, because recent studies have shown that waist circumference as an anthropometric surrogate correlates with erosive esophagitis.3Kang M.S. Park D.I. Oh S.Y. et al.Abdominal obesity is an independent risk factor for erosive esophagitis in a Korean population.J Gastroenterol Hepatol. 2007; 22: 1656-1661Google Scholar A large cross-sectional study of 80,110 individuals suggested also that abdominal diameter rather than BMI was associated with reflux-type symptoms and interestingly this correlation was much more pronounced in the white population and in male subjects.4Corley D.A. Kubo A. Zhao W. Abdominal obesity, ethnicity and gastro-oesophageal reflux symptoms.Gut. 2007; 56: 756-762Google Scholar Furthermore, a recent study demonstrated that visceral adipose tissue as assessed by computed tomography (CT) scan in 750 subjects correlated significantly with the presence of erosive esophagitis.5Chung S.J. Kim D. Park M.J. et al.Metabolic syndrome and visceral obesity as risk factors for reflux oesophagitis: a cross-sectional case-control study of 7078 Koreans undergoing health check-ups.Gut. 2008; 57: 1360-1365Google Scholar In this study, importantly, the metabolic syndrome was associated also with erosive esophagitis, indirectly suggesting that systemic low-grade inflammation as observed in obesity might interact with or even enhance other inflammatory conditions such as esophagitis. Therefore, obesity is associated with a significant higher rate of GERD symptoms, erosive esophagitis, and Barrett's esophagus, as well as esophageal adenocarcinoma.6Hampel H. Abraham N.S. El Serag H.B. Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications.Ann Intern Med. 2005; 143: 199-211Google Scholar, 7Corley D.A. Kubo A. Levin T.R. et al.Abdominal obesity and body mass index as risk factors for Barrett's esophagus.Gastroenterology. 2007; 133: 34-41Google Scholar, 8Edelstein Z.R. Farrow D.C. Bronner M.P. et al.Central adiposity and risk of Barrett's esophagus.Gastroenterology. 2007; 133: 403-411Google Scholar, 9Jacobson B.C. Chan A.T. Giovannucci E.L. et al.Body mass index and Barrett's oesophagus in women.Gut. 2009; 58: 1460-1466Google Scholar In addition to the established clinical associations between obesity and various diseases, recent research has identified that many of the metabolic/immune phenomena observed in obesity are mediated by a complex network of soluble mediators derived mainly from adipocytes. Adipose tissue is no longer considered to be an inert tissue functioning solely as energy storage, but has evolved as a critical factor in the regulation of many pathologic processes. Various products of the adipose tissue have been characterized and been termed adipocytokines.10Tilg H. Moschen A.R. Adipocytokines: mediators linking adipose tissue, inflammation and immunity.Nat Rev Immunol. 2006; 6: 772-783Google Scholar Adiponectin and leptin are the most abundant adipocytokines produced by adipocytes. Many other products of adipose tissue that have been previously characterized include various proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1, or plasminogen activator inhibitor 1, and several chemokines. Obesity is associated with a chronic inflammatory response characterized by abnormal cytokine production, increased synthesis of acute-phase reactants, such as C-reactive protein, and activation of inflammatory signaling pathways.10Tilg H. Moschen A.R. Adipocytokines: mediators linking adipose tissue, inflammation and immunity.Nat Rev Immunol. 2006; 6: 772-783Google Scholar Although there is no doubt that inflammatory pathways are activated in the visceral and subcutaneous adipose tissue itself in cases of obesity, the total contribution of adipocytes as a source of these circulating and systemically active cytokines, adipocytokines, and chemokines remains unclear. Obese adipose tissue, especially visceral adipose tissue, contains a considerable number of macrophages, making them an additional source of soluble mediators in the adipose tissue. Once macrophages are present and active, together with adipocytes and other cell types present in the adipose tissue, they might perpetuate a vicious cycle of macrophage recruitment and production of inflammatory cytokines. In this issue of Gastroenterology, Nam et al11Nam S.Y. Choi I.J. Ryu K.H. et al.Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women.Gastroenterology. 2010; 139: 1902-1911Google Scholar attempted to answer the critical question of whether abdominal visceral adipose tissue may be associated with presence of erosive esophagitis. In a large prospective study, 5329 participants underwent esophagogastroduodenoscopy and CT scan. Associations between erosive esophagitis and obesity included analysis of adipose visceral tissue, subcutaneous adipose tissue, BMI, waist circumference, and other risk factors. Importantly, the multivariate odds ratio for erosive esophagitis correlated nicely with visceral adipose tissue volume as the odds ratio was almost 3 for >1500 cm3 visceral adipose tissue volume. The 3 measures of obesity—BMI, waist circumference, and visceral adipose—tissue were associated significantly with erosive esophagitis in men, but only visceral adipose tissue showed such a correlation in women, making this parameter the strongest and most robust risk factor. A few other important findings from this large study appeared. (1) There was clear evidence that visceral adipose tissue volume correlated with the severity of esophagitis, suggesting that low-grade inflammation occurring in visceral adipose tissue might influence/enhance extent of inflammation at other locations, that is, distal esophagus. (2) GERD symptoms showed no association with visceral adipose tissue or any other marker of obesity. (3) The prevalence of Barrett's esophagus was 0.7% and did not show any correlation with visceral adipose tissue. (4) Current smoking, male gender, and the presence of hiatal hernia were other risk factors for erosive esophagitis. Strengths of this study are the use of experienced endoscopists involved in this large, prospective study, and the fact that endoscopy and CT scan using a 64-multidetector scan were performed in parallel. Chung et al5Chung S.J. Kim D. Park M.J. et al.Metabolic syndrome and visceral obesity as risk factors for reflux oesophagitis: a cross-sectional case-control study of 7078 Koreans undergoing health check-ups.Gut. 2008; 57: 1360-1365Google Scholar published recently a first cross-sectional study investigating 7078 subjects undergoing upper gastrointestinal endoscopy during a health check-up where they performed assessment of visceral and subcutaneous adipose tissue by CT scan. In this study, and this supports the findings by Nam et al,11Nam S.Y. Choi I.J. Ryu K.H. et al.Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women.Gastroenterology. 2010; 139: 1902-1911Google Scholar again only visceral but not subcutaneous adipose tissue was an independent risk factor for erosive esophagitis after adjusting for other risk factors such as smoking or BMI. In another small study, visceral obesity was quantitated by CT in 100 consecutive patients. These authors also described an association of erosive esophagitis with visceral but not subcutaneous fat.12Lee H.L. Eun C.S. Lee O.Y. et al.Association between erosive esophagitis and visceral fat accumulation quantified by abdominal CT scan.J Clin Gastroenterol. 2009; 43: 240-243Google Scholar Taken together, these studies demonstrate that indeed visceral adipose tissue might play a key role in the pathogenesis of obesity-related erosive esophagitis. Abdominal adiposity may affect the esophagogastric junction mechanically and via metabolic/inflammatory pathways. An obvious and commonly suggested pathogenetic mechanism could be a direct mechanical effect of abdominal obesity leading to an increased intra-abdominal pressure. An increase in BMI and to a lesser extent in waist circumference leads to an increase in acid reflux episodes and longer reflux episodes.13El Serag H.B. Ergun G.A. Pandolfino J. et al.Obesity increases oesophageal acid exposure.Gut. 2007; 56: 749-755Google Scholar Obese patients present with esophagogastric disruption as both BMI and waist circumference correlate with intragastric pressure and increased gastroesophageal pressure gradient.14Pandolfino J.E. El Serag H.B. Zhang Q. et al.Obesity: a challenge to esophagogastric junction integrity.Gastroenterology. 2006; 130: 639-649Abstract Full Text Full Text PDF Scopus (389) Google Scholar Obesity may also affect the lower esophageal sphincter as obesity correlates with an increased transient lower esophageal sphincter relaxation and an increased rate of transient lower esophageal sphincter relaxation with acid reflux.15Wu J.C. Mui L.M. Cheung C.M. et al.Obesity is associated with increased transient lower esophageal sphincter relaxation.Gastroenterology. 2007; 132: 883-889Abstract Full Text Full Text PDF Scopus (243) Google Scholar Nam et al11Nam S.Y. Choi I.J. Ryu K.H. et al.Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women.Gastroenterology. 2010; 139: 1902-1911Google Scholar did not assess intra-abdominal pressure and their excellent correlations between waist circumference and visceral fat suggest that the abdominal cavity may not represent a limited space. Furthermore, an increase in subcutaneous fat would also suggest an enhanced intra-abdominal pressure and there has been no association between subcutaneous fat and erosive esophagitis in both large trials.5Chung S.J. Kim D. Park M.J. et al.Metabolic syndrome and visceral obesity as risk factors for reflux oesophagitis: a cross-sectional case-control study of 7078 Koreans undergoing health check-ups.Gut. 2008; 57: 1360-1365Google Scholar, 11Nam S.Y. Choi I.J. Ryu K.H. et al.Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women.Gastroenterology. 2010; 139: 1902-1911Google Scholar Therefore, it is rather unlikely that simple mechanic aspects play the key role in the association between erosive esophagitis and amount of visceral adipose tissue. In this context, a more attractive interpretation of why visceral adipose tissue might favor development of erosive esophagitis is a “mediator-driven view.” The visceral adipose tissue as stated is a major (adipo)cytokine sink (eg, IL-1, IL-6, TNF-α, leptin, adiponectin, and others) and all these mediators likely exert systemic effects.16You T. Yang R. Lyles M.F. et al.Abdominal adipose tissue cytokine gene expression: relationship to obesity and metabolic risk factors.Am J Physiol Endocrinol Metab. 2005; 288: E741-E747Google Scholar Visceral fat volume directly correlates with serum levels of plasminogen activator inhibitor 1, TNF-α, and IL-6.17Alessi M.C. Bastelica D. Morange P. et al.Plasminogen activator inhibitor 1, transforming growth factor-beta1, and BMI are closely associated in human adipose tissue during morbid obesity.Diabetes. 2000; 49: 1374-1380Google Scholar, 18Bertin E. Nguyen P. Guenounou M. et al.Plasma levels of tumor necrosis factor-alpha (TNF-alpha) are essentially dependent on visceral fat amount in type 2 diabetic patients.Diabetes Metab. 2000; 26: 178-182Google Scholar, 19Park H.S. Park J.Y. Yu R. Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-alpha and IL-6.Diabetes Res Clin Pract. 2005; 69: 29-35Google Scholar Experimental evidence for an important role for this tissue comes from a study where removal of visceral fat in diabetic, obese rats improved insulin resistance and diabetes, clearly suggesting that the visceral adipose tissue maybe critically involved in major aspects of the metabolic syndrome.20Gabriely I. Ma X.H. Yang X.M. et al.Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process?.Diabetes. 2002; 51: 2951-2958Google Scholar Various (adipo)cytokines derived from the visceral adipose tissue may act systemically, influence and enhance inflammatory processes, and affect both gastric secretion and the esophagogastric junction. The proinflammatory cytokines IL-1 and TNF-α both stimulate gastrin release from human gastric antral fragments.21Beales I.L. Post L. Calam J. et al.Tumour necrosis factor alpha stimulates gastrin release from canine and human antral G cells: possible mechanism of the Helicobacter pylori-gastrin link.Eur J Clin Invest. 1996; 26: 609-611Google Scholar, 22Endo Y. Kumagai K. Induction by interleukin-1, tumor necrosis factor and lipopolysaccharides of histidine decarboxylase in the stomach and prolonged accumulation of gastric acid.Br J Pharmacol. 1998; 125: 842-848Google Scholar Furthermore, neutralization of TNF-α in Crohn's disease patients by a neutralizing antibody (infliximab) decreased gastrin release in response to bombesin.23Hopman W.P. de Jong D.J. Naber A.H. et al.Tumour necrosis factor alpha antibody affects gastrin release in Crohn disease.Scand J Gastroenterol. 2003; 38: 522-525Google Scholar In addition, the distal human esophagus produces cytokines in case of esophagitis and they negatively affect local contractility leading to motor disturbances.24Rieder F. Cheng L. Harnett K.M. et al.Gastroesophageal reflux disease-associated esophagitis induces endogenous cytokine production leading to motor abnormalities.Gastroenterology. 2007; 132: 154-165Google Scholar Direct effects of gastric exposure may be less important, as shown in a recent study by Souza et al,25Souza R.F. Huo X. Mittal V. et al.Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury.Gastroenterology. 2009; 137: 1776-1784Google Scholar who studied the development of esophagitis after esophagoduodenostomy—an animal model of reflux disease. The fact that esophageal inflammation initiates with lymphocyte infiltration in the submucosa not until day 3 and secondarily progresses to the mucosal surface suggests that cytokine-driven mechanisms might be of importance rather than a direct caustic effect owing to gastric acid exposure. The stomach is not only a source of the proinflammatory adipocytokine leptin,26Bado A. Levasseur S. Attoub S. et al.The stomach is a source of leptin.Nature. 1998; 394: 790-793Google Scholar but also a target for leptin; obesity is associated with increased serum leptin levels. Antral mucosa expresses functional leptin receptors and peripheral injection of leptin increased the release of gastrin.27Mix H. Widjaja A. Jandl O. et al.Expression of leptin and leptin receptor isoforms in the human stomach.Gut. 2000; 47: 481-486Google Scholar, 28Goiot H. Attoub S. Kermorgant S. et al.Antral mucosa expresses functional leptin receptors coupled to STAT-3 signaling, which is involved in the control of gastric secretions in the rat.Gastroenterology. 2001; 121: 1417-1427Abstract Full Text Full Text PDF Scopus (49) Google Scholar Serum levels of adiponectin, the potent anti-inflammatory adipocytokine, are decreased in obesity.29Scherer P.E. Williams S. Fogliano M. et al.A novel serum protein similar to C1q, produced exclusively in adipocytes.J Biol Chem. 1995; 270: 26746-26749Google Scholar This adipocytokine is almost exclusively derived from the adipose tissue. Adiponectin effects are mediated via its 2 receptors (types 1 and 2) and it has been shown that stomach and at least esophageal and junctional adenocarcinoma express the type 2 receptor.30Gonzalez C.R. Caminos J.E. Gallego R. et al.Adiponectin receptor 2 is regulated by nutritional status, leptin and pregnancy in a tissue-specific manner.Physiol Behav. 2010; 99: 91-99Google Scholar, 31Howard J.M. Beddy P. Ennis D. et al.Associations between leptin and adiponectin receptor upregulation, visceral obesity and tumour stage in oesophageal and junctional adenocarcinoma.Br J Surg. 2010; 97: 1020-1027Google Scholar Adiponectin circulates in various isoforms and some biological effects are isoform dependent. Whereas high-molecular weight adiponectin has more proinflammatory functions, the low-molecular weight isoform acts more as an anti-inflammatory.32Unger R.H. Scherer P.E. Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity.Trends Endocrinol Metab. 2010; 21: 345-352Google Scholar Importantly, a recent study has found that high levels of low-molecular weight adiponectin are associated with a decreased risk of Barrett's esophagus in patients with GERD,33Rubenstein J.H. Kao J.Y. Madanick R.D. et al.Association of adiponectin multimers with Barrett's esophagus.Gut. 2009; 58: 1583-1589Google Scholar thereby suggesting that a sufficient concentration of the anti-inflammatory adiponectin isoform might prevent inflammation at the esophagogastric junction. The prevalence of Barrett's esophagus is much greater in patients with the metabolic syndrome and associated with increased leptin levels and a trend toward decreased serum adiponectin levels.34Ryan A.M. Healy L.A. Power D.G. et al.Barrett esophagus: prevalence of central adiposity, metabolic syndrome, and a proinflammatory state.Ann Surg. 2008; 247: 909-915Google Scholar Although overall information on the interaction of various (adipo)cytokines with stomach, gastric secretion, and the esophagogastric junction is still in its infancy, such a “mediator-driven” concept for the striking correlation of erosive esophagitis with visceral adipose tissue might be attractive. It may well be that various mechanisms are involved in the pathogenesis of obesity-related erosive esophagitis: (1) Mechanical aspects/local injury by pathologic levels of esophageal acid exposure may act as a first hit followed by (2) proinflammatory signals derived from the visceral adipose tissue as a second hit (Figure 1). Abdominal Visceral Adipose Tissue Volume Is Associated With Increased Risk of Erosive Esophagitis in Men and WomenGastroenterologyVol. 139Issue 6PreviewData on the association between erosive esophagitis and obesity are inconsistent because of variations in study populations and methods used to determine obesity. Full-Text PDF