Gastric mucosal devitalization improves blood pressure, renin and cardiovascular lipid deposition in a rat model of obesity

Andreas Oberbach; Nadine Schlichting; Yvonne Kullnick; Marco Heinrich; Stefanie Lehmann; Ulf Retschlag; Maik Friedrich; Lea Fayad; Arne Dietrich; Mouen A. Khashab; Anthony N. Kalloo; Vivek Kumbhari

doi:10.1055/a-0990-9683

Endoscopy International Open, Table of Contents

CC BY-NC-ND 4.0 · Endosc Int Open 2019; 07(12): E1605-E1615
DOI: 10.1055/a-0990-9683

Original article

Gastric mucosal devitalization improves blood pressure, renin and cardiovascular lipid deposition in a rat model of obesity

Andreas Oberbach‡^*

¹Department of Medicine and Division of Gastroenterology and Hepatology. The Johns Hopkins Medical Institutions, Baltimore, Maryland, United States

²Fraunhofer Institute for Cell Therapy and Immunology, Department of Diagnostics, Leipzig, Germany

³Department of Cardiac Surgery, Ludwig-Maximilians-University, Munich, Germany

,

Nadine Schlichting‡^*

²Fraunhofer Institute for Cell Therapy and Immunology, Department of Diagnostics, Leipzig, Germany

⁴Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Leipzig University Hospital, Leipzig, Germany

,

Yvonne Kullnick

²Fraunhofer Institute for Cell Therapy and Immunology, Department of Diagnostics, Leipzig, Germany

,

Marco Heinrich

²Fraunhofer Institute for Cell Therapy and Immunology, Department of Diagnostics, Leipzig, Germany

,

Stefanie Lehmann

²Fraunhofer Institute for Cell Therapy and Immunology, Department of Diagnostics, Leipzig, Germany

⁵Department of Internal Medicine, University of Leipzig, Leipzig, Germany

,

Ulf Retschlag

⁴Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Leipzig University Hospital, Leipzig, Germany

⁶Integrated Research and Treatment Centre Obesity Diseases, Leipzig University, Leipzig, Germany

,

Maik Friedrich

²Fraunhofer Institute for Cell Therapy and Immunology, Department of Diagnostics, Leipzig, Germany

,

Lea Fayad

¹Department of Medicine and Division of Gastroenterology and Hepatology. The Johns Hopkins Medical Institutions, Baltimore, Maryland, United States

,

Arne Dietrich

⁶Integrated Research and Treatment Centre Obesity Diseases, Leipzig University, Leipzig, Germany

,

Mouen A. Khashab

¹Department of Medicine and Division of Gastroenterology and Hepatology. The Johns Hopkins Medical Institutions, Baltimore, Maryland, United States

,

Anthony N. Kalloo

¹Department of Medicine and Division of Gastroenterology and Hepatology. The Johns Hopkins Medical Institutions, Baltimore, Maryland, United States

,

Vivek Kumbhari

¹Department of Medicine and Division of Gastroenterology and Hepatology. The Johns Hopkins Medical Institutions, Baltimore, Maryland, United States

› Author Affiliations

Abstract

Background and study aims In lieu of the drawbacks of metabolic surgery, a method of mimicking resection of the gastric mucosa could be of value to those with obesity-related cardiovascular disease (CVD). Our study aims to investigate the effect of gastric mucosal devitalization (GMD) on blood pressure (BP) and cardiovascular lipid deposition in a rat model of obesity.

Methods GMD of 70 % of the stomach was achieved by argon plasma coagulation. GMD was compared to sleeve gastrectomy (SG) and sham (SH) in a high-fat-diet-induced rat model of obesity (48 rats). At 8 weeks, we measured noninvasive BP, renin, vessel relaxation and ghrelin receptor regulation in the aorta. In addition, we quantified cardiac lipid deposition and lipid droplet deposition in cardiac muscle and aorta.

Results GMD and SG were observed to have similar reductions in body weight, visceral adiposity, and serum lipid profile compared to SH rats. GMD resulted in a significant reduction in arterial BP compared to SH. Furthermore, there were significant reductions in plasma renin activity and percentage of phenylnephrine constriction to acetylcholine at the aortic ring in GMD rats compared to SH, providing insights into the mechanisms behind the reduced BP. Interestingly, the reduced BP occurred despite a reduction in endothelial ghrelin recteptor activation. Cardiac lipid content was significantly reduced in GMD rats. Lipid deposition, as illustrated by Nile Red stain, was reduced in cardiac muscle and the aorta.

Conclusion GMD resulted in a significant improvement in BP, renin and cardiovascular lipid deposition. GMD deserves further attention as a method of treating obesity-related CVD.

Full Text

References

References
1 Ogden CL, Fakhouri TH, Carroll MD. et al. Prevalence of Obesity Among Adults, by Household Income and Education - United States, 2011-2014. MMWR Morb Mortal Wkly Rep 2017; 66: 1369-1373
2 Jensen MD, Ryan DH, Apovian CM. et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol 2014; 63: 2985-3023
3 Blanco DG, Funes DR, Giambartolomei G. et al. Laparoscopic sleeve gastrectomy versus Roux-en-Y gastric bypass in cardiovascular risk reduction: A match control study. Surg Obes Relat Dis 2019; 15: 14-20
4 Shimada YJ, Gibo K, Tsugawa Y. et al. Bariatric surgery is associated with lower risk of acute care use for cardiovascular disease in obese adults. Cardiovasc Res 2019; 115: 800-806
5 Chambers AP, Jessen L, Ryan KK. et al. Weight-independent changes in blood glucose homeostasis after gastric bypass or vertical sleeve gastrectomy in rats. Gastroenterology 2011; 141: 950-958
6 Stefater MA, Sandoval DA, Chambers AP. et al. Sleeve gastrectomy in rats improves postprandial lipid clearance by reducing intestinal triglyceride secretion. Gastroenterology 2011; 141: 939-949 e1-4
7 Zechner JF, Mirshahi UL, Satapati S. et al. Weight-independent effects of roux-en-Y gastric bypass on glucose homeostasis via melanocortin-4 receptors in mice and humans. Gastroenterology 2013; 144: 580-590 e7
8 Stevens J, Oakkar EE, Cui Z. et al. US adults recommended for weight reduction by 1998 and 2013 obesity guidelines, NHANES 2007-2012. Obesity 2015; 23: 527-531
9 Estimate of Bariatric Surgery Numbers, 2011-2017. 2018 https://asmbs.org/resources/estimate-of-bariatric-surgery-numbers
10 Acosta A, Abu Dayyeh BK, Port JD. et al. Recent advances in clinical practice challenges and opportunities in the management of obesity. Gut 2014; 63: 687-695
11 Ryan KK, Tremaroli V, Clemmensen C. et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 2014; 509: 183-188
12 Oberbach A, Schlichting N, Heinrich M. et al. Gastric mucosal devitalization reduces adiposity and improves lipid and glucose metabolism in obese rats. Gastrointest Endosc 2018; 87: 288-299 e6
13 Kumbhari V, Lehmann S, Schlichting N. et al. Gastric mucosal devitalization is safe and effective in reducing body weight and visceral adiposity in a porcine model. Gastrointest Endosc 2018; 88: 175-184 e1
14 Estimate of Bariatric Surgery Numbers, 2011-2017. 2018 https://asmbs.org/resources/estimate-of-bariatric-surgery-numbers
15 Whelton PK, Carey RM, Aronow WS. et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018; 71: 2199-2269
16 Sletten AC, Peterson LR, Schaffer JE. Manifestations and mechanisms of myocardial lipotoxicity in obesity. J Intern Med 2018; 284: 478-491
17 Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes. https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=celex%3A32010L0063
18 Oberbach A, Schlichting N, Heinrich M. et al. Weight loss surgery improves the metabolic status in an obese rat model but does not affect bladder fibrosis associated with high fat diet feeding. Int J Obes (Lond) 2014; 38: 1061-1067
19 Oberbach A, Jehmlich N, Schlichting N. et al. Molecular fingerprint of high fat diet induced urinary bladder metabolic dysfunction in a rat model. PLoS One 2013; 8: e66636
20 Saydah S, Bullard KM, Cheng Y. et al. Trends in cardiovascular disease risk factors by obesity level in adults in the United States, NHANES 1999-2010. Obesity (Silver Spring) 2014; 22: 1888-1895
21 Harsha DW, Bray GA. Weight loss and blood pressure control (Pro). Hypertension 2008; 51: 1420-1425 ; discussion 5
22 Hubert HB, Feinleib M, McNamara PM. et al. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 1983; 67: 968-977
23 Huang Z, Willett WC, Manson JE. et al. Body weight, weight change, and risk for hypertension in women. Ann Intern Med 1998; 128: 81-88
24 Hall JE. The kidney, hypertension, and obesity. Hypertension 2003; 41: 625-633
25 Lim SS, Vos T, Flaxman AD. et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2224-2260
26 Lewington S, Clarke R, Qizilbash N. et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360: 1903-1913
27 Rapsomaniki E, Timmis A, George J. et al. Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1.25 million people. Lancet 2014; 383: 1899-1911
28 Juonala M, Magnussen CG, Berenson GS. et al. Childhood adiposity, adult adiposity, and cardiovascular risk factors. N Engl J Med 2011; 365: 1876-1885
29 Wang JG, Staessen JA, Franklin SS. et al. Systolic and diastolic blood pressure lowering as determinants of cardiovascular outcome. Hypertension 2005; 45: 907-913
30 Turnbull F, Neal B, Algert C. et al. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med 2005; 165: 1410-1419
31 Schmieder RE, Hilgers KF, Schlaich MP. et al. Renin-angiotensin system and cardiovascular risk. Lancet 2007; 369: 1208-1219
32 Marcheselli S, Micieli G. Renin-angiotensin system and stroke. Neurol Sci 2008; 29: S277-S278
33 Joseph JJ, Echouffo Tcheugui JB, Effoe VS. et al. Renin-angiotensin-aldosterone system, glucose metabolism and incident Type 2 diabetes mellitus: MESA. J Am Heart Assoc 2018; 7: e009890
34 Engeli S, Bohnke J, Gorzelniak K. et al. Weight loss and the renin-angiotensin-aldosterone system. Hypertension 2005; 45: 356-362
35 Mao Y, Tokudome T, Kishimoto I. Ghrelin and blood pressure regulation. Curr Hypertens Rep 2016; 18: 15
36 Goldberg IJ, Reue K, Abumrad NA. et al. Deciphering the role of lipid droplets in cardiovascular disease: a report from the 2017 National Heart, Lung, and Blood Institute Workshop. Circulation 2018; 138: 305-315
37 Lang PD, Insull Jr W. Lipid droplets in atherosclerotic fatty streaks of human aorta. J Clin Invest 1970; 49: 1479-1488
38 Itabe H, Yamaguchi T, Nimura S. et al. Perilipins: a diversity of intracellular lipid droplet proteins. Lipids Health Dis 2017; 16: 83
39 Mazzali G, Fantin F, Zoico E. et al. Heart fat infiltration in subjects with and without coronary artery disease. J Clin Endocrinol Metab 2015; 100: 3364-3371
40 Conte M, Franceschi C, Sandri M. et al. Perilipin 2 and age-related metabolic diseases: a new perspective. Trends Endocrinol Metab 2016; 27: 893-903
41 Bosma M, Hesselink MK, Sparks LM. et al. Perilipin 2 improves insulin sensitivity in skeletal muscle despite elevated intramuscular lipid levels. Diabetes 2012; 61: 2679-2690

Supplementary Material

Supplementary material