Free Fatty Acids Link Metabolism and Regulation of the Insulin-Sensitizing Fibroblast Growth Factor-21
Free Fatty Acids Link Metabolism and Regulation of the Insulin-Sensitizing Fibroblast Growth Factor-21 Knut Mai 1 , Janin Andres 1 , Katrin Biedasek 1 , Jessica Weicht 1 , Thomas Bobbert 1 , Markus Sabath 2 , Sabine Meinus 1 , Franziska Reinecke 1 , Matthias Möhlig 1 , Martin O. Weickert 2 , Markus...
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| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2009-07, Vol.58 (7), p.1532-1538 |
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| creator | MAI, Knut ANDRES, Janin CLEMENZ, Markus PFEIFFER, Andreas F. H KINTSCHER, Ulrich SPULER, Simone SPRANGER, Joachim BIEDASEK, Katrin WEICHT, Jessica BOBBERT, Thomas SABATH, Markus MEINUS, Sabine REINECKE, Franziska MÖHLIG, Matthias WEICKERT, Martin O |
| description | Free Fatty Acids Link Metabolism and Regulation of the Insulin-Sensitizing Fibroblast Growth Factor-21
Knut Mai 1 ,
Janin Andres 1 ,
Katrin Biedasek 1 ,
Jessica Weicht 1 ,
Thomas Bobbert 1 ,
Markus Sabath 2 ,
Sabine Meinus 1 ,
Franziska Reinecke 1 ,
Matthias Möhlig 1 ,
Martin O. Weickert 2 ,
Markus Clemenz 3 ,
Andreas F.H. Pfeiffer 1 , 2 ,
Ulrich Kintscher 3 ,
Simone Spuler 4 and
Joachim Spranger 1 , 2
1 Department of Endocrinology, Diabetes and Nutrition, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin,
Germany;
2 German Institute of Nutrition, Department of Clinical Nutrition, Potsdam, Germany;
3 Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Berlin, Germany;
4 Muscle Research Unit, Experimental and Clinical Research Center, Charite-Universitätsmedizin Berlin, Campus Buch, Berlin,
Germany.
Corresponding author: Joachim Spranger, joachim.spranger{at}charite.de .
Abstract
OBJECTIVE Fibroblast growth factor (FGF)-21 improves insulin sensitivity and lipid metabolism in obese or diabetic animal models, while
human studies revealed increased FGF-21 levels in obesity and type 2 diabetes. Given that FGF-21 has been suggested to be
a peroxisome proliferator–activator receptor (PPAR) α–dependent regulator of fasting metabolism, we hypothesized that free
fatty acids (FFAs), natural agonists of PPARα, might modify FGF-21 levels.
RESEARCH DESIGN AND METHODS The effect of fatty acids on FGF-21 was investigated in vitro in HepG2 cells. Within a randomized controlled trial, the effects
of elevated FFAs were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals,
the effect of insulin was analyzed using an hyperinsulinemic-euglycemic clamp and the effect of PPARγ activation was studied
subsequently in a rosiglitazone treatment trial over 8 weeks.
RESULTS Oleate and linoleate increased FGF-21 expression and secretion in a PPARα-dependent fashion, as demonstrated by small-interfering
RNA–induced PPARα knockdown, while palmitate had no effect. In vivo, lipid infusion induced an increase of circulating FGF-21
in humans, and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed. An artificial
hyperinsulinemia, which was induced to delineate the potential interaction between elevated FFAs and hyperinsulinemia, revealed
that hyperinsulinemia also increased FGF-21 levels in vivo, while rosiglitazone treatment had no effect |
| doi_str_mv | 10.2337/db08-1775 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmed_primary_19401423</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A203230058</galeid><sourcerecordid>A203230058</sourcerecordid><originalsourceid>FETCH-LOGICAL-c681t-3ac1870992e860d6b0d2e42d9b19dde5d641a8a0c2414bf5f74e0bd28ca15b813</originalsourceid><addsrcrecordid>eNptkl2LEzEUhgdR3Lp64R-QIHghMmuS-UjmRijF1oXKgh_gXcjHmWnWabImGdf115vSsmuhnIuEc57zcnh5i-IlwRe0qth7ozAvCWPNo2JGuqorK8p-PC5mGBOa-x07K57FeI0xbnM9Lc5IV2NS02pW9MsAgJYypTs019ZEtLbuJ_oMSSo_2rhF0hn0BYZplMl6h3yP0gbQpYvTaF35FVy0yf61bkBLq4JXo4wJrYK_TZusq5MPJSXPiye9HCO8OLznxfflx2-LT-X6anW5mK9L3XKSykpqwhnuOgq8xaZV2FCoqekU6YyBxrQ1kVxiTWtSq77pWQ1YGcq1JI3ipDovPux1bya1BaPBpSBHcRPsVoY74aUVxxNnN2LwvwVtu443dRZ4fRAI_tcEMYlrPwWXbxaUtDXjGcxQuYcGOYKwrvdZSw_gIEt6B73N7TnFFa0wbnjmL07wuQxsrT658PZoITMJ_qRBTjEKvlofs-UpVvtxhAFEtndxdVJbBx9jgP7eHYLFLk5iFyexi1NmX_1v5wN5yE8G3hwAGbUc-yCdtvGeo4TVLBubuXd7bmOHza0NIIyVChLEh0_DBROkyXf-A5gG3vE</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>216478269</pqid></control><display><type>article</type><title>Free Fatty Acids Link Metabolism and Regulation of the Insulin-Sensitizing Fibroblast Growth Factor-21</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>MAI, Knut ; ANDRES, Janin ; CLEMENZ, Markus ; PFEIFFER, Andreas F. H ; KINTSCHER, Ulrich ; SPULER, Simone ; SPRANGER, Joachim ; BIEDASEK, Katrin ; WEICHT, Jessica ; BOBBERT, Thomas ; SABATH, Markus ; MEINUS, Sabine ; REINECKE, Franziska ; MÖHLIG, Matthias ; WEICKERT, Martin O</creator><creatorcontrib>MAI, Knut ; ANDRES, Janin ; CLEMENZ, Markus ; PFEIFFER, Andreas F. H ; KINTSCHER, Ulrich ; SPULER, Simone ; SPRANGER, Joachim ; BIEDASEK, Katrin ; WEICHT, Jessica ; BOBBERT, Thomas ; SABATH, Markus ; MEINUS, Sabine ; REINECKE, Franziska ; MÖHLIG, Matthias ; WEICKERT, Martin O</creatorcontrib><description>Free Fatty Acids Link Metabolism and Regulation of the Insulin-Sensitizing Fibroblast Growth Factor-21
Knut Mai 1 ,
Janin Andres 1 ,
Katrin Biedasek 1 ,
Jessica Weicht 1 ,
Thomas Bobbert 1 ,
Markus Sabath 2 ,
Sabine Meinus 1 ,
Franziska Reinecke 1 ,
Matthias Möhlig 1 ,
Martin O. Weickert 2 ,
Markus Clemenz 3 ,
Andreas F.H. Pfeiffer 1 , 2 ,
Ulrich Kintscher 3 ,
Simone Spuler 4 and
Joachim Spranger 1 , 2
1 Department of Endocrinology, Diabetes and Nutrition, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin,
Germany;
2 German Institute of Nutrition, Department of Clinical Nutrition, Potsdam, Germany;
3 Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Berlin, Germany;
4 Muscle Research Unit, Experimental and Clinical Research Center, Charite-Universitätsmedizin Berlin, Campus Buch, Berlin,
Germany.
Corresponding author: Joachim Spranger, joachim.spranger{at}charite.de .
Abstract
OBJECTIVE Fibroblast growth factor (FGF)-21 improves insulin sensitivity and lipid metabolism in obese or diabetic animal models, while
human studies revealed increased FGF-21 levels in obesity and type 2 diabetes. Given that FGF-21 has been suggested to be
a peroxisome proliferator–activator receptor (PPAR) α–dependent regulator of fasting metabolism, we hypothesized that free
fatty acids (FFAs), natural agonists of PPARα, might modify FGF-21 levels.
RESEARCH DESIGN AND METHODS The effect of fatty acids on FGF-21 was investigated in vitro in HepG2 cells. Within a randomized controlled trial, the effects
of elevated FFAs were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals,
the effect of insulin was analyzed using an hyperinsulinemic-euglycemic clamp and the effect of PPARγ activation was studied
subsequently in a rosiglitazone treatment trial over 8 weeks.
RESULTS Oleate and linoleate increased FGF-21 expression and secretion in a PPARα-dependent fashion, as demonstrated by small-interfering
RNA–induced PPARα knockdown, while palmitate had no effect. In vivo, lipid infusion induced an increase of circulating FGF-21
in humans, and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed. An artificial
hyperinsulinemia, which was induced to delineate the potential interaction between elevated FFAs and hyperinsulinemia, revealed
that hyperinsulinemia also increased FGF-21 levels in vivo, while rosiglitazone treatment had no effect.
CONCLUSIONS The results presented here offer a mechanism explaining the induction of the metabolic regulator FGF-21 in the fasting situation
but also in type 2 diabetes and obesity.
Footnotes
Clinical trial reg. no. NCT00473603, clinicaltrials.gov.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received December 22, 2008.
Accepted April 14, 2009.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
© 2009 by the American Diabetes Association.</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db08-1775</identifier><identifier>PMID: 19401423</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>Alexandria, VA: American Diabetes Association</publisher><subject>Biological and medical sciences ; Cell Line ; Cholesterol ; Clinical trials ; Complications and side effects ; Cross-sectional studies ; Diabetes ; Diabetes Mellitus, Type 2 - complications ; Diabetes Mellitus, Type 2 - drug therapy ; Diabetes Mellitus, Type 2 - metabolism ; Diabetes. Impaired glucose tolerance ; Endocrine disorders ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Fasting - physiology ; Fatty acid metabolism ; Fatty acids ; Fatty Acids, Nonesterified - metabolism ; Female ; Fibroblast growth factors ; Fibroblast Growth Factors - genetics ; Fibroblast Growth Factors - metabolism ; Fibroblasts ; Gene Expression Regulation - drug effects ; Genetic aspects ; Glucose ; Glucose Clamp Technique ; Glycerol ; Glycerol - pharmacology ; Growth factors ; Heart failure ; Homeostasis ; Humans ; Hyperinsulinism - metabolism ; Hyperinsulinism - physiopathology ; Hypoglycemic Agents - therapeutic use ; Insulin resistance ; Lecithins - pharmacology ; Lipids ; Male ; Medical sciences ; Metabolism ; Musculoskeletal system ; Obesity ; Obesity - complications ; Obesity - metabolism ; Original ; Physiological aspects ; PPAR alpha - genetics ; PPAR alpha - physiology ; PPAR gamma - genetics ; PPAR gamma - physiology ; Reference Values ; Research design ; RNA, Messenger - genetics ; Systemic diseases ; Thiazolidinediones - therapeutic use ; Type 2 diabetes</subject><ispartof>Diabetes (New York, N.Y.), 2009-07, Vol.58 (7), p.1532-1538</ispartof><rights>2009 INIST-CNRS</rights><rights>COPYRIGHT 2009 American Diabetes Association</rights><rights>Copyright American Diabetes Association Jul 2009</rights><rights>2009 by the American Diabetes Association.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c681t-3ac1870992e860d6b0d2e42d9b19dde5d641a8a0c2414bf5f74e0bd28ca15b813</citedby><cites>FETCH-LOGICAL-c681t-3ac1870992e860d6b0d2e42d9b19dde5d641a8a0c2414bf5f74e0bd28ca15b813</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699854/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699854/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21747998$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19401423$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>MAI, Knut</creatorcontrib><creatorcontrib>ANDRES, Janin</creatorcontrib><creatorcontrib>CLEMENZ, Markus</creatorcontrib><creatorcontrib>PFEIFFER, Andreas F. H</creatorcontrib><creatorcontrib>KINTSCHER, Ulrich</creatorcontrib><creatorcontrib>SPULER, Simone</creatorcontrib><creatorcontrib>SPRANGER, Joachim</creatorcontrib><creatorcontrib>BIEDASEK, Katrin</creatorcontrib><creatorcontrib>WEICHT, Jessica</creatorcontrib><creatorcontrib>BOBBERT, Thomas</creatorcontrib><creatorcontrib>SABATH, Markus</creatorcontrib><creatorcontrib>MEINUS, Sabine</creatorcontrib><creatorcontrib>REINECKE, Franziska</creatorcontrib><creatorcontrib>MÖHLIG, Matthias</creatorcontrib><creatorcontrib>WEICKERT, Martin O</creatorcontrib><title>Free Fatty Acids Link Metabolism and Regulation of the Insulin-Sensitizing Fibroblast Growth Factor-21</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Free Fatty Acids Link Metabolism and Regulation of the Insulin-Sensitizing Fibroblast Growth Factor-21
Knut Mai 1 ,
Janin Andres 1 ,
Katrin Biedasek 1 ,
Jessica Weicht 1 ,
Thomas Bobbert 1 ,
Markus Sabath 2 ,
Sabine Meinus 1 ,
Franziska Reinecke 1 ,
Matthias Möhlig 1 ,
Martin O. Weickert 2 ,
Markus Clemenz 3 ,
Andreas F.H. Pfeiffer 1 , 2 ,
Ulrich Kintscher 3 ,
Simone Spuler 4 and
Joachim Spranger 1 , 2
1 Department of Endocrinology, Diabetes and Nutrition, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin,
Germany;
2 German Institute of Nutrition, Department of Clinical Nutrition, Potsdam, Germany;
3 Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Berlin, Germany;
4 Muscle Research Unit, Experimental and Clinical Research Center, Charite-Universitätsmedizin Berlin, Campus Buch, Berlin,
Germany.
Corresponding author: Joachim Spranger, joachim.spranger{at}charite.de .
Abstract
OBJECTIVE Fibroblast growth factor (FGF)-21 improves insulin sensitivity and lipid metabolism in obese or diabetic animal models, while
human studies revealed increased FGF-21 levels in obesity and type 2 diabetes. Given that FGF-21 has been suggested to be
a peroxisome proliferator–activator receptor (PPAR) α–dependent regulator of fasting metabolism, we hypothesized that free
fatty acids (FFAs), natural agonists of PPARα, might modify FGF-21 levels.
RESEARCH DESIGN AND METHODS The effect of fatty acids on FGF-21 was investigated in vitro in HepG2 cells. Within a randomized controlled trial, the effects
of elevated FFAs were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals,
the effect of insulin was analyzed using an hyperinsulinemic-euglycemic clamp and the effect of PPARγ activation was studied
subsequently in a rosiglitazone treatment trial over 8 weeks.
RESULTS Oleate and linoleate increased FGF-21 expression and secretion in a PPARα-dependent fashion, as demonstrated by small-interfering
RNA–induced PPARα knockdown, while palmitate had no effect. In vivo, lipid infusion induced an increase of circulating FGF-21
in humans, and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed. An artificial
hyperinsulinemia, which was induced to delineate the potential interaction between elevated FFAs and hyperinsulinemia, revealed
that hyperinsulinemia also increased FGF-21 levels in vivo, while rosiglitazone treatment had no effect.
CONCLUSIONS The results presented here offer a mechanism explaining the induction of the metabolic regulator FGF-21 in the fasting situation
but also in type 2 diabetes and obesity.
Footnotes
Clinical trial reg. no. NCT00473603, clinicaltrials.gov.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received December 22, 2008.
Accepted April 14, 2009.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
© 2009 by the American Diabetes Association.</description><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Cholesterol</subject><subject>Clinical trials</subject><subject>Complications and side effects</subject><subject>Cross-sectional studies</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Type 2 - complications</subject><subject>Diabetes Mellitus, Type 2 - drug therapy</subject><subject>Diabetes Mellitus, Type 2 - metabolism</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Endocrine disorders</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>Fasting - physiology</subject><subject>Fatty acid metabolism</subject><subject>Fatty acids</subject><subject>Fatty Acids, Nonesterified - metabolism</subject><subject>Female</subject><subject>Fibroblast growth factors</subject><subject>Fibroblast Growth Factors - genetics</subject><subject>Fibroblast Growth Factors - metabolism</subject><subject>Fibroblasts</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Genetic aspects</subject><subject>Glucose</subject><subject>Glucose Clamp Technique</subject><subject>Glycerol</subject><subject>Glycerol - pharmacology</subject><subject>Growth factors</subject><subject>Heart failure</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Hyperinsulinism - metabolism</subject><subject>Hyperinsulinism - physiopathology</subject><subject>Hypoglycemic Agents - therapeutic use</subject><subject>Insulin resistance</subject><subject>Lecithins - pharmacology</subject><subject>Lipids</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metabolism</subject><subject>Musculoskeletal system</subject><subject>Obesity</subject><subject>Obesity - complications</subject><subject>Obesity - metabolism</subject><subject>Original</subject><subject>Physiological aspects</subject><subject>PPAR alpha - genetics</subject><subject>PPAR alpha - physiology</subject><subject>PPAR gamma - genetics</subject><subject>PPAR gamma - physiology</subject><subject>Reference Values</subject><subject>Research design</subject><subject>RNA, Messenger - genetics</subject><subject>Systemic diseases</subject><subject>Thiazolidinediones - therapeutic use</subject><subject>Type 2 diabetes</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNptkl2LEzEUhgdR3Lp64R-QIHghMmuS-UjmRijF1oXKgh_gXcjHmWnWabImGdf115vSsmuhnIuEc57zcnh5i-IlwRe0qth7ozAvCWPNo2JGuqorK8p-PC5mGBOa-x07K57FeI0xbnM9Lc5IV2NS02pW9MsAgJYypTs019ZEtLbuJ_oMSSo_2rhF0hn0BYZplMl6h3yP0gbQpYvTaF35FVy0yf61bkBLq4JXo4wJrYK_TZusq5MPJSXPiye9HCO8OLznxfflx2-LT-X6anW5mK9L3XKSykpqwhnuOgq8xaZV2FCoqekU6YyBxrQ1kVxiTWtSq77pWQ1YGcq1JI3ipDovPux1bya1BaPBpSBHcRPsVoY74aUVxxNnN2LwvwVtu443dRZ4fRAI_tcEMYlrPwWXbxaUtDXjGcxQuYcGOYKwrvdZSw_gIEt6B73N7TnFFa0wbnjmL07wuQxsrT658PZoITMJ_qRBTjEKvlofs-UpVvtxhAFEtndxdVJbBx9jgP7eHYLFLk5iFyexi1NmX_1v5wN5yE8G3hwAGbUc-yCdtvGeo4TVLBubuXd7bmOHza0NIIyVChLEh0_DBROkyXf-A5gG3vE</recordid><startdate>20090701</startdate><enddate>20090701</enddate><creator>MAI, Knut</creator><creator>ANDRES, Janin</creator><creator>CLEMENZ, Markus</creator><creator>PFEIFFER, Andreas F. H</creator><creator>KINTSCHER, Ulrich</creator><creator>SPULER, Simone</creator><creator>SPRANGER, Joachim</creator><creator>BIEDASEK, Katrin</creator><creator>WEICHT, Jessica</creator><creator>BOBBERT, Thomas</creator><creator>SABATH, Markus</creator><creator>MEINUS, Sabine</creator><creator>REINECKE, Franziska</creator><creator>MÖHLIG, Matthias</creator><creator>WEICKERT, Martin O</creator><general>American Diabetes Association</general><scope>IQODW</scope><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>8GL</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7P</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>S0X</scope><scope>5PM</scope></search><sort><creationdate>20090701</creationdate><title>Free Fatty Acids Link Metabolism and Regulation of the Insulin-Sensitizing Fibroblast Growth Factor-21</title><author>MAI, Knut ; ANDRES, Janin ; CLEMENZ, Markus ; PFEIFFER, Andreas F. H ; KINTSCHER, Ulrich ; SPULER, Simone ; SPRANGER, Joachim ; BIEDASEK, Katrin ; WEICHT, Jessica ; BOBBERT, Thomas ; SABATH, Markus ; MEINUS, Sabine ; REINECKE, Franziska ; MÖHLIG, Matthias ; WEICKERT, Martin O</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c681t-3ac1870992e860d6b0d2e42d9b19dde5d641a8a0c2414bf5f74e0bd28ca15b813</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>Cholesterol</topic><topic>Clinical trials</topic><topic>Complications and side effects</topic><topic>Cross-sectional studies</topic><topic>Diabetes</topic><topic>Diabetes Mellitus, Type 2 - complications</topic><topic>Diabetes Mellitus, Type 2 - drug therapy</topic><topic>Diabetes Mellitus, Type 2 - metabolism</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>Endocrine disorders</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Etiopathogenesis. Screening. Investigations. Target tissue resistance</topic><topic>Fasting - physiology</topic><topic>Fatty acid metabolism</topic><topic>Fatty acids</topic><topic>Fatty Acids, Nonesterified - metabolism</topic><topic>Female</topic><topic>Fibroblast growth factors</topic><topic>Fibroblast Growth Factors - genetics</topic><topic>Fibroblast Growth Factors - metabolism</topic><topic>Fibroblasts</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Genetic aspects</topic><topic>Glucose</topic><topic>Glucose Clamp Technique</topic><topic>Glycerol</topic><topic>Glycerol - pharmacology</topic><topic>Growth factors</topic><topic>Heart failure</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Hyperinsulinism - metabolism</topic><topic>Hyperinsulinism - physiopathology</topic><topic>Hypoglycemic Agents - therapeutic use</topic><topic>Insulin resistance</topic><topic>Lecithins - pharmacology</topic><topic>Lipids</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Metabolism</topic><topic>Musculoskeletal system</topic><topic>Obesity</topic><topic>Obesity - complications</topic><topic>Obesity - metabolism</topic><topic>Original</topic><topic>Physiological aspects</topic><topic>PPAR alpha - genetics</topic><topic>PPAR alpha - physiology</topic><topic>PPAR gamma - genetics</topic><topic>PPAR gamma - physiology</topic><topic>Reference Values</topic><topic>Research design</topic><topic>RNA, Messenger - genetics</topic><topic>Systemic diseases</topic><topic>Thiazolidinediones - therapeutic use</topic><topic>Type 2 diabetes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>MAI, Knut</creatorcontrib><creatorcontrib>ANDRES, Janin</creatorcontrib><creatorcontrib>CLEMENZ, Markus</creatorcontrib><creatorcontrib>PFEIFFER, Andreas F. H</creatorcontrib><creatorcontrib>KINTSCHER, Ulrich</creatorcontrib><creatorcontrib>SPULER, Simone</creatorcontrib><creatorcontrib>SPRANGER, Joachim</creatorcontrib><creatorcontrib>BIEDASEK, Katrin</creatorcontrib><creatorcontrib>WEICHT, Jessica</creatorcontrib><creatorcontrib>BOBBERT, Thomas</creatorcontrib><creatorcontrib>SABATH, Markus</creatorcontrib><creatorcontrib>MEINUS, Sabine</creatorcontrib><creatorcontrib>REINECKE, Franziska</creatorcontrib><creatorcontrib>MÖHLIG, Matthias</creatorcontrib><creatorcontrib>WEICKERT, Martin O</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: High School</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>SciTech Premium Collection</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>SIRS Editorial</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>MAI, Knut</au><au>ANDRES, Janin</au><au>CLEMENZ, Markus</au><au>PFEIFFER, Andreas F. H</au><au>KINTSCHER, Ulrich</au><au>SPULER, Simone</au><au>SPRANGER, Joachim</au><au>BIEDASEK, Katrin</au><au>WEICHT, Jessica</au><au>BOBBERT, Thomas</au><au>SABATH, Markus</au><au>MEINUS, Sabine</au><au>REINECKE, Franziska</au><au>MÖHLIG, Matthias</au><au>WEICKERT, Martin O</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Free Fatty Acids Link Metabolism and Regulation of the Insulin-Sensitizing Fibroblast Growth Factor-21</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2009-07-01</date><risdate>2009</risdate><volume>58</volume><issue>7</issue><spage>1532</spage><epage>1538</epage><pages>1532-1538</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>Free Fatty Acids Link Metabolism and Regulation of the Insulin-Sensitizing Fibroblast Growth Factor-21
Knut Mai 1 ,
Janin Andres 1 ,
Katrin Biedasek 1 ,
Jessica Weicht 1 ,
Thomas Bobbert 1 ,
Markus Sabath 2 ,
Sabine Meinus 1 ,
Franziska Reinecke 1 ,
Matthias Möhlig 1 ,
Martin O. Weickert 2 ,
Markus Clemenz 3 ,
Andreas F.H. Pfeiffer 1 , 2 ,
Ulrich Kintscher 3 ,
Simone Spuler 4 and
Joachim Spranger 1 , 2
1 Department of Endocrinology, Diabetes and Nutrition, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin,
Germany;
2 German Institute of Nutrition, Department of Clinical Nutrition, Potsdam, Germany;
3 Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Berlin, Germany;
4 Muscle Research Unit, Experimental and Clinical Research Center, Charite-Universitätsmedizin Berlin, Campus Buch, Berlin,
Germany.
Corresponding author: Joachim Spranger, joachim.spranger{at}charite.de .
Abstract
OBJECTIVE Fibroblast growth factor (FGF)-21 improves insulin sensitivity and lipid metabolism in obese or diabetic animal models, while
human studies revealed increased FGF-21 levels in obesity and type 2 diabetes. Given that FGF-21 has been suggested to be
a peroxisome proliferator–activator receptor (PPAR) α–dependent regulator of fasting metabolism, we hypothesized that free
fatty acids (FFAs), natural agonists of PPARα, might modify FGF-21 levels.
RESEARCH DESIGN AND METHODS The effect of fatty acids on FGF-21 was investigated in vitro in HepG2 cells. Within a randomized controlled trial, the effects
of elevated FFAs were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals,
the effect of insulin was analyzed using an hyperinsulinemic-euglycemic clamp and the effect of PPARγ activation was studied
subsequently in a rosiglitazone treatment trial over 8 weeks.
RESULTS Oleate and linoleate increased FGF-21 expression and secretion in a PPARα-dependent fashion, as demonstrated by small-interfering
RNA–induced PPARα knockdown, while palmitate had no effect. In vivo, lipid infusion induced an increase of circulating FGF-21
in humans, and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed. An artificial
hyperinsulinemia, which was induced to delineate the potential interaction between elevated FFAs and hyperinsulinemia, revealed
that hyperinsulinemia also increased FGF-21 levels in vivo, while rosiglitazone treatment had no effect.
CONCLUSIONS The results presented here offer a mechanism explaining the induction of the metabolic regulator FGF-21 in the fasting situation
but also in type 2 diabetes and obesity.
Footnotes
Clinical trial reg. no. NCT00473603, clinicaltrials.gov.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received December 22, 2008.
Accepted April 14, 2009.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
© 2009 by the American Diabetes Association.</abstract><cop>Alexandria, VA</cop><pub>American Diabetes Association</pub><pmid>19401423</pmid><doi>10.2337/db08-1775</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0012-1797 |
| ispartof | Diabetes (New York, N.Y.), 2009-07, Vol.58 (7), p.1532-1538 |
| issn | 0012-1797 1939-327X |
| language | eng |
| recordid | cdi_pubmed_primary_19401423 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Biological and medical sciences Cell Line Cholesterol Clinical trials Complications and side effects Cross-sectional studies Diabetes Diabetes Mellitus, Type 2 - complications Diabetes Mellitus, Type 2 - drug therapy Diabetes Mellitus, Type 2 - metabolism Diabetes. Impaired glucose tolerance Endocrine disorders Endocrine pancreas. Apud cells (diseases) Endocrinopathies Etiopathogenesis. Screening. Investigations. Target tissue resistance Fasting - physiology Fatty acid metabolism Fatty acids Fatty Acids, Nonesterified - metabolism Female Fibroblast growth factors Fibroblast Growth Factors - genetics Fibroblast Growth Factors - metabolism Fibroblasts Gene Expression Regulation - drug effects Genetic aspects Glucose Glucose Clamp Technique Glycerol Glycerol - pharmacology Growth factors Heart failure Homeostasis Humans Hyperinsulinism - metabolism Hyperinsulinism - physiopathology Hypoglycemic Agents - therapeutic use Insulin resistance Lecithins - pharmacology Lipids Male Medical sciences Metabolism Musculoskeletal system Obesity Obesity - complications Obesity - metabolism Original Physiological aspects PPAR alpha - genetics PPAR alpha - physiology PPAR gamma - genetics PPAR gamma - physiology Reference Values Research design RNA, Messenger - genetics Systemic diseases Thiazolidinediones - therapeutic use Type 2 diabetes |
| title | Free Fatty Acids Link Metabolism and Regulation of the Insulin-Sensitizing Fibroblast Growth Factor-21 |
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