Rapid and Body Weight–Independent Improvement of Endothelial and High-Density Lipoprotein Function After Roux-en-Y Gastric Bypass: Role of Glucagon-Like Peptide-1
BACKGROUND—Roux-en-Y gastric bypass (RYGB) reduces body weight and cardiovascular mortality in morbidly obese patients. Glucagon-like peptide-1 (GLP-1) seems to mediate the metabolic benefits of RYGB partly in a weight loss–independent manner. The present study investigated in rats and patients whet...
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| Veröffentlicht in: | Circulation (New York, N.Y.) N.Y.), 2015-03, Vol.131 (10), p.871-881 |
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| creator | Osto, Elena Doytcheva, Petia Corteville, Caroline Bueter, Marco Dörig, Claudia Stivala, Simona Buhmann, Helena Colin, Sophie Rohrer, Lucia Hasballa, Reda Tailleux, Anne Wolfrum, Christian Tona, Francesco Manz, Jasmin Vetter, Diana Spliethoff, Kerstin Vanhoutte, Paul M Landmesser, Ulf Pattou, Francois Staels, Bart Matter, Christian M Lutz, Thomas A Lüscher, Thomas F |
| description | BACKGROUND—Roux-en-Y gastric bypass (RYGB) reduces body weight and cardiovascular mortality in morbidly obese patients. Glucagon-like peptide-1 (GLP-1) seems to mediate the metabolic benefits of RYGB partly in a weight loss–independent manner. The present study investigated in rats and patients whether obesity-induced endothelial and high-density lipoprotein (HDL) dysfunction is rapidly improved after RYGB via a GLP-1–dependent mechanism.
METHODS AND RESULTS—Eight days after RYGB in diet-induced obese rats, higher plasma levels of bile acids and GLP-1 were associated with improved endothelium-dependent relaxation compared with sham-operated controls fed ad libitum and sham-operated rats that were weight matched to those undergoing RYGB. Compared with the sham-operated rats, RYGB improved nitric oxide (NO) bioavailability resulting from higher endothelial Akt/NO synthase activation, reduced c-Jun amino terminal kinase phosphorylation, and decreased oxidative stress. The protective effects of RYGB were prevented by the GLP-1 receptor antagonist exendin9-39 (10 μg·kg·h). Furthermore, in patients and rats, RYGB rapidly reversed HDL dysfunction and restored the endothelium-protective properties of the lipoprotein, including endothelial NO synthase activation, NO production, and anti-inflammatory, antiapoptotic, and antioxidant effects. Finally, RYGB restored HDL-mediated cholesterol efflux capacity. To demonstrate the role of increased GLP-1 signaling, sham-operated control rats were treated for 8 days with the GLP-1 analog liraglutide (0.2 mg/kg twice daily), which restored NO bioavailability and improved endothelium-dependent relaxations and HDL endothelium-protective properties, mimicking the effects of RYGB.
CONCLUSIONS—RYGB rapidly reverses obesity-induced endothelial dysfunction and restores the endothelium-protective properties of HDL via a GLP-1–mediated mechanism. The present translational findings in rats and patients unmask novel, weight-independent mechanisms of cardiovascular protection in morbid obesity. |
| doi_str_mv | 10.1161/CIRCULATIONAHA.114.011791 |
| format | Article |
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METHODS AND RESULTS—Eight days after RYGB in diet-induced obese rats, higher plasma levels of bile acids and GLP-1 were associated with improved endothelium-dependent relaxation compared with sham-operated controls fed ad libitum and sham-operated rats that were weight matched to those undergoing RYGB. Compared with the sham-operated rats, RYGB improved nitric oxide (NO) bioavailability resulting from higher endothelial Akt/NO synthase activation, reduced c-Jun amino terminal kinase phosphorylation, and decreased oxidative stress. The protective effects of RYGB were prevented by the GLP-1 receptor antagonist exendin9-39 (10 μg·kg·h). Furthermore, in patients and rats, RYGB rapidly reversed HDL dysfunction and restored the endothelium-protective properties of the lipoprotein, including endothelial NO synthase activation, NO production, and anti-inflammatory, antiapoptotic, and antioxidant effects. Finally, RYGB restored HDL-mediated cholesterol efflux capacity. To demonstrate the role of increased GLP-1 signaling, sham-operated control rats were treated for 8 days with the GLP-1 analog liraglutide (0.2 mg/kg twice daily), which restored NO bioavailability and improved endothelium-dependent relaxations and HDL endothelium-protective properties, mimicking the effects of RYGB.
CONCLUSIONS—RYGB rapidly reverses obesity-induced endothelial dysfunction and restores the endothelium-protective properties of HDL via a GLP-1–mediated mechanism. The present translational findings in rats and patients unmask novel, weight-independent mechanisms of cardiovascular protection in morbid obesity.</description><identifier>ISSN: 0009-7322</identifier><identifier>EISSN: 1524-4539</identifier><identifier>DOI: 10.1161/CIRCULATIONAHA.114.011791</identifier><identifier>PMID: 25673670</identifier><language>eng</language><publisher>United States: by the American College of Cardiology Foundation and the American Heart Association, Inc</publisher><subject>Adult ; Animals ; Antioxidants - physiology ; Body Weight - physiology ; Case-Control Studies ; Cells, Cultured ; Diet, High-Fat - adverse effects ; Disease Models, Animal ; Endothelium, Vascular - pathology ; Endothelium, Vascular - physiology ; Female ; Gastric Bypass ; Glucagon-Like Peptide 1 - physiology ; Humans ; Lipoproteins, HDL - physiology ; Male ; Nitric Oxide - physiology ; Obesity - physiopathology ; Obesity - surgery ; Oxidative Stress - physiology ; Proto-Oncogene Proteins c-akt - physiology ; Rats ; Rats, Wistar ; Signal Transduction ; Treatment Outcome ; Weight Loss - physiology</subject><ispartof>Circulation (New York, N.Y.), 2015-03, Vol.131 (10), p.871-881</ispartof><rights>2015 by the American College of Cardiology Foundation and the American Heart Association, Inc.</rights><rights>2015 American Heart Association, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3626-7dbd9922fa48195b44de76e8c869f4828754ebf9a61880e41ae4fc52545de5e43</citedby><cites>FETCH-LOGICAL-c3626-7dbd9922fa48195b44de76e8c869f4828754ebf9a61880e41ae4fc52545de5e43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3687,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25673670$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Osto, Elena</creatorcontrib><creatorcontrib>Doytcheva, Petia</creatorcontrib><creatorcontrib>Corteville, Caroline</creatorcontrib><creatorcontrib>Bueter, Marco</creatorcontrib><creatorcontrib>Dörig, Claudia</creatorcontrib><creatorcontrib>Stivala, Simona</creatorcontrib><creatorcontrib>Buhmann, Helena</creatorcontrib><creatorcontrib>Colin, Sophie</creatorcontrib><creatorcontrib>Rohrer, Lucia</creatorcontrib><creatorcontrib>Hasballa, Reda</creatorcontrib><creatorcontrib>Tailleux, Anne</creatorcontrib><creatorcontrib>Wolfrum, Christian</creatorcontrib><creatorcontrib>Tona, Francesco</creatorcontrib><creatorcontrib>Manz, Jasmin</creatorcontrib><creatorcontrib>Vetter, Diana</creatorcontrib><creatorcontrib>Spliethoff, Kerstin</creatorcontrib><creatorcontrib>Vanhoutte, Paul M</creatorcontrib><creatorcontrib>Landmesser, Ulf</creatorcontrib><creatorcontrib>Pattou, Francois</creatorcontrib><creatorcontrib>Staels, Bart</creatorcontrib><creatorcontrib>Matter, Christian M</creatorcontrib><creatorcontrib>Lutz, Thomas A</creatorcontrib><creatorcontrib>Lüscher, Thomas F</creatorcontrib><title>Rapid and Body Weight–Independent Improvement of Endothelial and High-Density Lipoprotein Function After Roux-en-Y Gastric Bypass: Role of Glucagon-Like Peptide-1</title><title>Circulation (New York, N.Y.)</title><addtitle>Circulation</addtitle><description>BACKGROUND—Roux-en-Y gastric bypass (RYGB) reduces body weight and cardiovascular mortality in morbidly obese patients. Glucagon-like peptide-1 (GLP-1) seems to mediate the metabolic benefits of RYGB partly in a weight loss–independent manner. The present study investigated in rats and patients whether obesity-induced endothelial and high-density lipoprotein (HDL) dysfunction is rapidly improved after RYGB via a GLP-1–dependent mechanism.
METHODS AND RESULTS—Eight days after RYGB in diet-induced obese rats, higher plasma levels of bile acids and GLP-1 were associated with improved endothelium-dependent relaxation compared with sham-operated controls fed ad libitum and sham-operated rats that were weight matched to those undergoing RYGB. Compared with the sham-operated rats, RYGB improved nitric oxide (NO) bioavailability resulting from higher endothelial Akt/NO synthase activation, reduced c-Jun amino terminal kinase phosphorylation, and decreased oxidative stress. The protective effects of RYGB were prevented by the GLP-1 receptor antagonist exendin9-39 (10 μg·kg·h). Furthermore, in patients and rats, RYGB rapidly reversed HDL dysfunction and restored the endothelium-protective properties of the lipoprotein, including endothelial NO synthase activation, NO production, and anti-inflammatory, antiapoptotic, and antioxidant effects. Finally, RYGB restored HDL-mediated cholesterol efflux capacity. To demonstrate the role of increased GLP-1 signaling, sham-operated control rats were treated for 8 days with the GLP-1 analog liraglutide (0.2 mg/kg twice daily), which restored NO bioavailability and improved endothelium-dependent relaxations and HDL endothelium-protective properties, mimicking the effects of RYGB.
CONCLUSIONS—RYGB rapidly reverses obesity-induced endothelial dysfunction and restores the endothelium-protective properties of HDL via a GLP-1–mediated mechanism. The present translational findings in rats and patients unmask novel, weight-independent mechanisms of cardiovascular protection in morbid obesity.</description><subject>Adult</subject><subject>Animals</subject><subject>Antioxidants - physiology</subject><subject>Body Weight - physiology</subject><subject>Case-Control Studies</subject><subject>Cells, Cultured</subject><subject>Diet, High-Fat - adverse effects</subject><subject>Disease Models, Animal</subject><subject>Endothelium, Vascular - pathology</subject><subject>Endothelium, Vascular - physiology</subject><subject>Female</subject><subject>Gastric Bypass</subject><subject>Glucagon-Like Peptide 1 - physiology</subject><subject>Humans</subject><subject>Lipoproteins, HDL - physiology</subject><subject>Male</subject><subject>Nitric Oxide - physiology</subject><subject>Obesity - physiopathology</subject><subject>Obesity - surgery</subject><subject>Oxidative Stress - physiology</subject><subject>Proto-Oncogene Proteins c-akt - physiology</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Signal Transduction</subject><subject>Treatment Outcome</subject><subject>Weight Loss - physiology</subject><issn>0009-7322</issn><issn>1524-4539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkU9u1DAUhyMEokPhCsjs2LjYju0k7KZDOxMpomjUCrGKPPFLxzSx09ihzK536BU4GSfB0ylIbPzn-fs9y_6S5B0lJ5RK-mFRrhdX1fyyvPg8X81jjZ8QSrOCPktmVDCOuUiL58mMEFLgLGXsKHnl_fe4lWkmXiZHTMgslRmZJb_WajAaKavRqdM79BXM9Tb8vn8orYYB4mADKvthdD-g369di86sdmELnVHdY3AVI_gTWG_CDlVmcJEOYCw6n2wTjLNo3gYY0dpNPzFY_A0tlQ-jadDpblDef4wnHew7L7upUdfO4srcAPoCQzAaMH2dvGhV5-HN03ycXJ2fXS5WuLpYlot5hZtUMokzvdFFwVireE4LseFcQyYhb3JZtDxneSY4bNpCSZrnBDhVwNtGMMGFBgE8PU7eH_rGB9xO4EPdG99A1ykLbvI1lZJxlhNKIloc0GZ03o_Q1sNoejXuakrqvaT6f0mxxuuDpJh9-3TNtOlB_0v-tRIBfgDuXBc_zt900x2M9RZUF7Z11EhSQjPMCBUkpYRg8qj2Dw5moQI</recordid><startdate>20150310</startdate><enddate>20150310</enddate><creator>Osto, Elena</creator><creator>Doytcheva, Petia</creator><creator>Corteville, Caroline</creator><creator>Bueter, Marco</creator><creator>Dörig, Claudia</creator><creator>Stivala, Simona</creator><creator>Buhmann, Helena</creator><creator>Colin, Sophie</creator><creator>Rohrer, Lucia</creator><creator>Hasballa, Reda</creator><creator>Tailleux, Anne</creator><creator>Wolfrum, Christian</creator><creator>Tona, Francesco</creator><creator>Manz, Jasmin</creator><creator>Vetter, Diana</creator><creator>Spliethoff, Kerstin</creator><creator>Vanhoutte, Paul M</creator><creator>Landmesser, Ulf</creator><creator>Pattou, Francois</creator><creator>Staels, Bart</creator><creator>Matter, Christian M</creator><creator>Lutz, Thomas A</creator><creator>Lüscher, Thomas F</creator><general>by the American College of Cardiology Foundation and the American Heart Association, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20150310</creationdate><title>Rapid and Body Weight–Independent Improvement of Endothelial and High-Density Lipoprotein Function After Roux-en-Y Gastric Bypass: Role of Glucagon-Like Peptide-1</title><author>Osto, Elena ; Doytcheva, Petia ; Corteville, Caroline ; Bueter, Marco ; Dörig, Claudia ; Stivala, Simona ; Buhmann, Helena ; Colin, Sophie ; Rohrer, Lucia ; Hasballa, Reda ; Tailleux, Anne ; Wolfrum, Christian ; Tona, Francesco ; Manz, Jasmin ; Vetter, Diana ; Spliethoff, Kerstin ; Vanhoutte, Paul M ; Landmesser, Ulf ; Pattou, Francois ; Staels, Bart ; Matter, Christian M ; Lutz, Thomas A ; Lüscher, Thomas F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3626-7dbd9922fa48195b44de76e8c869f4828754ebf9a61880e41ae4fc52545de5e43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adult</topic><topic>Animals</topic><topic>Antioxidants - physiology</topic><topic>Body Weight - physiology</topic><topic>Case-Control Studies</topic><topic>Cells, Cultured</topic><topic>Diet, High-Fat - adverse effects</topic><topic>Disease Models, Animal</topic><topic>Endothelium, Vascular - pathology</topic><topic>Endothelium, Vascular - physiology</topic><topic>Female</topic><topic>Gastric Bypass</topic><topic>Glucagon-Like Peptide 1 - physiology</topic><topic>Humans</topic><topic>Lipoproteins, HDL - physiology</topic><topic>Male</topic><topic>Nitric Oxide - physiology</topic><topic>Obesity - physiopathology</topic><topic>Obesity - surgery</topic><topic>Oxidative Stress - physiology</topic><topic>Proto-Oncogene Proteins c-akt - physiology</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Signal Transduction</topic><topic>Treatment Outcome</topic><topic>Weight Loss - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Osto, Elena</creatorcontrib><creatorcontrib>Doytcheva, Petia</creatorcontrib><creatorcontrib>Corteville, Caroline</creatorcontrib><creatorcontrib>Bueter, Marco</creatorcontrib><creatorcontrib>Dörig, Claudia</creatorcontrib><creatorcontrib>Stivala, Simona</creatorcontrib><creatorcontrib>Buhmann, Helena</creatorcontrib><creatorcontrib>Colin, Sophie</creatorcontrib><creatorcontrib>Rohrer, Lucia</creatorcontrib><creatorcontrib>Hasballa, Reda</creatorcontrib><creatorcontrib>Tailleux, Anne</creatorcontrib><creatorcontrib>Wolfrum, Christian</creatorcontrib><creatorcontrib>Tona, Francesco</creatorcontrib><creatorcontrib>Manz, Jasmin</creatorcontrib><creatorcontrib>Vetter, Diana</creatorcontrib><creatorcontrib>Spliethoff, Kerstin</creatorcontrib><creatorcontrib>Vanhoutte, Paul M</creatorcontrib><creatorcontrib>Landmesser, Ulf</creatorcontrib><creatorcontrib>Pattou, Francois</creatorcontrib><creatorcontrib>Staels, Bart</creatorcontrib><creatorcontrib>Matter, Christian M</creatorcontrib><creatorcontrib>Lutz, Thomas A</creatorcontrib><creatorcontrib>Lüscher, Thomas F</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Circulation (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Osto, Elena</au><au>Doytcheva, Petia</au><au>Corteville, Caroline</au><au>Bueter, Marco</au><au>Dörig, Claudia</au><au>Stivala, Simona</au><au>Buhmann, Helena</au><au>Colin, Sophie</au><au>Rohrer, Lucia</au><au>Hasballa, Reda</au><au>Tailleux, Anne</au><au>Wolfrum, Christian</au><au>Tona, Francesco</au><au>Manz, Jasmin</au><au>Vetter, Diana</au><au>Spliethoff, Kerstin</au><au>Vanhoutte, Paul M</au><au>Landmesser, Ulf</au><au>Pattou, Francois</au><au>Staels, Bart</au><au>Matter, Christian M</au><au>Lutz, Thomas A</au><au>Lüscher, Thomas F</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rapid and Body Weight–Independent Improvement of Endothelial and High-Density Lipoprotein Function After Roux-en-Y Gastric Bypass: Role of Glucagon-Like Peptide-1</atitle><jtitle>Circulation (New York, N.Y.)</jtitle><addtitle>Circulation</addtitle><date>2015-03-10</date><risdate>2015</risdate><volume>131</volume><issue>10</issue><spage>871</spage><epage>881</epage><pages>871-881</pages><issn>0009-7322</issn><eissn>1524-4539</eissn><abstract>BACKGROUND—Roux-en-Y gastric bypass (RYGB) reduces body weight and cardiovascular mortality in morbidly obese patients. Glucagon-like peptide-1 (GLP-1) seems to mediate the metabolic benefits of RYGB partly in a weight loss–independent manner. The present study investigated in rats and patients whether obesity-induced endothelial and high-density lipoprotein (HDL) dysfunction is rapidly improved after RYGB via a GLP-1–dependent mechanism.
METHODS AND RESULTS—Eight days after RYGB in diet-induced obese rats, higher plasma levels of bile acids and GLP-1 were associated with improved endothelium-dependent relaxation compared with sham-operated controls fed ad libitum and sham-operated rats that were weight matched to those undergoing RYGB. Compared with the sham-operated rats, RYGB improved nitric oxide (NO) bioavailability resulting from higher endothelial Akt/NO synthase activation, reduced c-Jun amino terminal kinase phosphorylation, and decreased oxidative stress. The protective effects of RYGB were prevented by the GLP-1 receptor antagonist exendin9-39 (10 μg·kg·h). Furthermore, in patients and rats, RYGB rapidly reversed HDL dysfunction and restored the endothelium-protective properties of the lipoprotein, including endothelial NO synthase activation, NO production, and anti-inflammatory, antiapoptotic, and antioxidant effects. Finally, RYGB restored HDL-mediated cholesterol efflux capacity. To demonstrate the role of increased GLP-1 signaling, sham-operated control rats were treated for 8 days with the GLP-1 analog liraglutide (0.2 mg/kg twice daily), which restored NO bioavailability and improved endothelium-dependent relaxations and HDL endothelium-protective properties, mimicking the effects of RYGB.
CONCLUSIONS—RYGB rapidly reverses obesity-induced endothelial dysfunction and restores the endothelium-protective properties of HDL via a GLP-1–mediated mechanism. The present translational findings in rats and patients unmask novel, weight-independent mechanisms of cardiovascular protection in morbid obesity.</abstract><cop>United States</cop><pub>by the American College of Cardiology Foundation and the American Heart Association, Inc</pub><pmid>25673670</pmid><doi>10.1161/CIRCULATIONAHA.114.011791</doi><tpages>11</tpages></addata></record> |
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| ispartof | Circulation (New York, N.Y.), 2015-03, Vol.131 (10), p.871-881 |
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| language | eng |
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| source | MEDLINE; American Heart Association Journals; Journals@Ovid Complete; EZB-FREE-00999 freely available EZB journals |
| subjects | Adult Animals Antioxidants - physiology Body Weight - physiology Case-Control Studies Cells, Cultured Diet, High-Fat - adverse effects Disease Models, Animal Endothelium, Vascular - pathology Endothelium, Vascular - physiology Female Gastric Bypass Glucagon-Like Peptide 1 - physiology Humans Lipoproteins, HDL - physiology Male Nitric Oxide - physiology Obesity - physiopathology Obesity - surgery Oxidative Stress - physiology Proto-Oncogene Proteins c-akt - physiology Rats Rats, Wistar Signal Transduction Treatment Outcome Weight Loss - physiology |
| title | Rapid and Body Weight–Independent Improvement of Endothelial and High-Density Lipoprotein Function After Roux-en-Y Gastric Bypass: Role of Glucagon-Like Peptide-1 |
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