Immunological blockade of adipocyte inflammation caused by increased matrix metalloproteinase‐cleaved osteopontin in obesity
Objective Osteopontin (OPN) is upregulated in adipose tissue (AT) in obesity and contributes to subclinical inflammation, adipocyte dysfunction, and insulin resistance. OPN effects can be increased by cleavage by matrix metalloproteinases (MMP). This study aimed at investigating the presence of OPN...
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| Veröffentlicht in: | Obesity (Silver Spring, Md.) Md.), 2015-04, Vol.23 (4), p.779-785 |
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| container_title | Obesity (Silver Spring, Md.) |
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| creator | Leitner, Lukas Schuch, Karina Jürets, Alexander Itariu, Bianca K. Keck, Maike Grablowitz, Viktor Aszmann, Oskar C. Prager, Gerhard Staffler, Günther Zeyda, Maximilian Stulnig, Thomas M. |
| description | Objective
Osteopontin (OPN) is upregulated in adipose tissue (AT) in obesity and contributes to subclinical inflammation, adipocyte dysfunction, and insulin resistance. OPN effects can be increased by cleavage by matrix metalloproteinases (MMP). This study aimed at investigating the presence of OPN cleavage products in human AT in obesity and their impact on adipocyte function and immunological blockade of these effects.
Methods
AT of severely obese and control donors was investigated for OPN and MMP expression and the presence of OPN cleavage fragments. Primary adipocytes were isolated from human donors for in vitro investigation of cleaved OPN effects.
Results
OPN and MMP‐9 expression was highly correlated in AT from obese donors, and increased levels of cleaved OPN were detected in AT from obese individuals. The in vitro effect of OPN on adipocyte inflammation and insulin resistance was enhanced by protease cleavage, which could finally be blocked with a monoclonal antibody directed against the MMP cleavage site of OPN.
Conclusions
These findings show that MMP cleavage of OPN in AT occurs in obesity, thereby enhancing OPN's inflammatory and pro‐diabetic activity on adipocytes. Specifically targeting MMP‐cleaved OPN opens avenues for prevention and treatment of obesity‐induced type 2 diabetes. |
| doi_str_mv | 10.1002/oby.21024 |
| format | Article |
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Osteopontin (OPN) is upregulated in adipose tissue (AT) in obesity and contributes to subclinical inflammation, adipocyte dysfunction, and insulin resistance. OPN effects can be increased by cleavage by matrix metalloproteinases (MMP). This study aimed at investigating the presence of OPN cleavage products in human AT in obesity and their impact on adipocyte function and immunological blockade of these effects.
Methods
AT of severely obese and control donors was investigated for OPN and MMP expression and the presence of OPN cleavage fragments. Primary adipocytes were isolated from human donors for in vitro investigation of cleaved OPN effects.
Results
OPN and MMP‐9 expression was highly correlated in AT from obese donors, and increased levels of cleaved OPN were detected in AT from obese individuals. The in vitro effect of OPN on adipocyte inflammation and insulin resistance was enhanced by protease cleavage, which could finally be blocked with a monoclonal antibody directed against the MMP cleavage site of OPN.
Conclusions
These findings show that MMP cleavage of OPN in AT occurs in obesity, thereby enhancing OPN's inflammatory and pro‐diabetic activity on adipocytes. Specifically targeting MMP‐cleaved OPN opens avenues for prevention and treatment of obesity‐induced type 2 diabetes.</description><identifier>ISSN: 1930-7381</identifier><identifier>EISSN: 1930-739X</identifier><identifier>DOI: 10.1002/oby.21024</identifier><identifier>PMID: 25776538</identifier><language>eng</language><publisher>United States: Blackwell Publishing Ltd</publisher><subject>Adipocytes ; Adipocytes - metabolism ; Adipose Tissue - metabolism ; Binding sites ; Cytokines ; Diabetes ; Gastrointestinal surgery ; Gene expression ; Humans ; Insulin Resistance ; Matrix Metalloproteinase 9 - metabolism ; Metabolism ; Obesity ; Obesity - immunology ; Obesity - physiopathology ; Obesity - prevention & control ; Osteopontin - metabolism ; Proteins ; Rodents ; Studies</subject><ispartof>Obesity (Silver Spring, Md.), 2015-04, Vol.23 (4), p.779-785</ispartof><rights>2015 The Obesity Society</rights><rights>2015 The Obesity Society.</rights><rights>Copyright Blackwell Publishing Ltd. Apr 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4544-c4128e712be7102eee9420607fccead8aedfc82b8e5328f12ae9a314cf6607c63</citedby><cites>FETCH-LOGICAL-c4544-c4128e712be7102eee9420607fccead8aedfc82b8e5328f12ae9a314cf6607c63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Foby.21024$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Foby.21024$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,1427,27901,27902,45550,45551,46384,46808</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25776538$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Leitner, Lukas</creatorcontrib><creatorcontrib>Schuch, Karina</creatorcontrib><creatorcontrib>Jürets, Alexander</creatorcontrib><creatorcontrib>Itariu, Bianca K.</creatorcontrib><creatorcontrib>Keck, Maike</creatorcontrib><creatorcontrib>Grablowitz, Viktor</creatorcontrib><creatorcontrib>Aszmann, Oskar C.</creatorcontrib><creatorcontrib>Prager, Gerhard</creatorcontrib><creatorcontrib>Staffler, Günther</creatorcontrib><creatorcontrib>Zeyda, Maximilian</creatorcontrib><creatorcontrib>Stulnig, Thomas M.</creatorcontrib><title>Immunological blockade of adipocyte inflammation caused by increased matrix metalloproteinase‐cleaved osteopontin in obesity</title><title>Obesity (Silver Spring, Md.)</title><addtitle>Obesity (Silver Spring)</addtitle><description>Objective
Osteopontin (OPN) is upregulated in adipose tissue (AT) in obesity and contributes to subclinical inflammation, adipocyte dysfunction, and insulin resistance. OPN effects can be increased by cleavage by matrix metalloproteinases (MMP). This study aimed at investigating the presence of OPN cleavage products in human AT in obesity and their impact on adipocyte function and immunological blockade of these effects.
Methods
AT of severely obese and control donors was investigated for OPN and MMP expression and the presence of OPN cleavage fragments. Primary adipocytes were isolated from human donors for in vitro investigation of cleaved OPN effects.
Results
OPN and MMP‐9 expression was highly correlated in AT from obese donors, and increased levels of cleaved OPN were detected in AT from obese individuals. The in vitro effect of OPN on adipocyte inflammation and insulin resistance was enhanced by protease cleavage, which could finally be blocked with a monoclonal antibody directed against the MMP cleavage site of OPN.
Conclusions
These findings show that MMP cleavage of OPN in AT occurs in obesity, thereby enhancing OPN's inflammatory and pro‐diabetic activity on adipocytes. Specifically targeting MMP‐cleaved OPN opens avenues for prevention and treatment of obesity‐induced type 2 diabetes.</description><subject>Adipocytes</subject><subject>Adipocytes - metabolism</subject><subject>Adipose Tissue - metabolism</subject><subject>Binding sites</subject><subject>Cytokines</subject><subject>Diabetes</subject><subject>Gastrointestinal surgery</subject><subject>Gene expression</subject><subject>Humans</subject><subject>Insulin Resistance</subject><subject>Matrix Metalloproteinase 9 - metabolism</subject><subject>Metabolism</subject><subject>Obesity</subject><subject>Obesity - immunology</subject><subject>Obesity - physiopathology</subject><subject>Obesity - prevention & control</subject><subject>Osteopontin - metabolism</subject><subject>Proteins</subject><subject>Rodents</subject><subject>Studies</subject><issn>1930-7381</issn><issn>1930-739X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kbtOwzAUhi0EoqUw8AIoEgsMLbZzc0aouFSq1AUkmCLHOUEudhziBMiCeASekSfBJaUDEsu5fufXkX6EDgmeEIzpmcm6CSWYBltoSBIfj2M_ud_e1IwM0J61S4yDCIdkFw1oGMdR6LMhep9p3ZZGmUcpuPIyZcQTz8EzhcdzWRnRNeDJslBca95IU3qCtxZyL-vcWNTAV41b1fLN09BwpUxVmwZk6TZfH59CAX9xiLENmMqUjSzdoWcysLLp9tFOwZWFg3Ueobury9vpzXi-uJ5Nz-djEYRB4CKhDGJCMxcwBYAkoDjCcSEE8JxxyAvBaMYg9CkrCOWQcJ8EoogcJCJ_hE56Xffbcwu2SbW0ApTiJZjWpiSK4iQimCUOPf6DLk1bl-47R8Uspj7G2FGnPSVqY20NRVrVUvO6SwlOV6akzpT0xxTHHq0V20xDviF_XXDAWQ-8SgXd_0rp4uKhl_wGWgSaPg</recordid><startdate>201504</startdate><enddate>201504</enddate><creator>Leitner, Lukas</creator><creator>Schuch, Karina</creator><creator>Jürets, Alexander</creator><creator>Itariu, Bianca K.</creator><creator>Keck, Maike</creator><creator>Grablowitz, Viktor</creator><creator>Aszmann, Oskar C.</creator><creator>Prager, Gerhard</creator><creator>Staffler, Günther</creator><creator>Zeyda, Maximilian</creator><creator>Stulnig, Thomas M.</creator><general>Blackwell Publishing Ltd</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>K9.</scope><scope>7X8</scope></search><sort><creationdate>201504</creationdate><title>Immunological blockade of adipocyte inflammation caused by increased matrix metalloproteinase‐cleaved osteopontin in obesity</title><author>Leitner, Lukas ; Schuch, Karina ; Jürets, Alexander ; Itariu, Bianca K. ; Keck, Maike ; Grablowitz, Viktor ; Aszmann, Oskar C. ; Prager, Gerhard ; Staffler, Günther ; Zeyda, Maximilian ; Stulnig, Thomas M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4544-c4128e712be7102eee9420607fccead8aedfc82b8e5328f12ae9a314cf6607c63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adipocytes</topic><topic>Adipocytes - metabolism</topic><topic>Adipose Tissue - metabolism</topic><topic>Binding sites</topic><topic>Cytokines</topic><topic>Diabetes</topic><topic>Gastrointestinal surgery</topic><topic>Gene expression</topic><topic>Humans</topic><topic>Insulin Resistance</topic><topic>Matrix Metalloproteinase 9 - metabolism</topic><topic>Metabolism</topic><topic>Obesity</topic><topic>Obesity - immunology</topic><topic>Obesity - physiopathology</topic><topic>Obesity - prevention & control</topic><topic>Osteopontin - metabolism</topic><topic>Proteins</topic><topic>Rodents</topic><topic>Studies</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Leitner, Lukas</creatorcontrib><creatorcontrib>Schuch, Karina</creatorcontrib><creatorcontrib>Jürets, Alexander</creatorcontrib><creatorcontrib>Itariu, Bianca K.</creatorcontrib><creatorcontrib>Keck, Maike</creatorcontrib><creatorcontrib>Grablowitz, Viktor</creatorcontrib><creatorcontrib>Aszmann, Oskar C.</creatorcontrib><creatorcontrib>Prager, Gerhard</creatorcontrib><creatorcontrib>Staffler, Günther</creatorcontrib><creatorcontrib>Zeyda, Maximilian</creatorcontrib><creatorcontrib>Stulnig, Thomas M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Obesity (Silver Spring, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Leitner, Lukas</au><au>Schuch, Karina</au><au>Jürets, Alexander</au><au>Itariu, Bianca K.</au><au>Keck, Maike</au><au>Grablowitz, Viktor</au><au>Aszmann, Oskar C.</au><au>Prager, Gerhard</au><au>Staffler, Günther</au><au>Zeyda, Maximilian</au><au>Stulnig, Thomas M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Immunological blockade of adipocyte inflammation caused by increased matrix metalloproteinase‐cleaved osteopontin in obesity</atitle><jtitle>Obesity (Silver Spring, Md.)</jtitle><addtitle>Obesity (Silver Spring)</addtitle><date>2015-04</date><risdate>2015</risdate><volume>23</volume><issue>4</issue><spage>779</spage><epage>785</epage><pages>779-785</pages><issn>1930-7381</issn><eissn>1930-739X</eissn><abstract>Objective
Osteopontin (OPN) is upregulated in adipose tissue (AT) in obesity and contributes to subclinical inflammation, adipocyte dysfunction, and insulin resistance. OPN effects can be increased by cleavage by matrix metalloproteinases (MMP). This study aimed at investigating the presence of OPN cleavage products in human AT in obesity and their impact on adipocyte function and immunological blockade of these effects.
Methods
AT of severely obese and control donors was investigated for OPN and MMP expression and the presence of OPN cleavage fragments. Primary adipocytes were isolated from human donors for in vitro investigation of cleaved OPN effects.
Results
OPN and MMP‐9 expression was highly correlated in AT from obese donors, and increased levels of cleaved OPN were detected in AT from obese individuals. The in vitro effect of OPN on adipocyte inflammation and insulin resistance was enhanced by protease cleavage, which could finally be blocked with a monoclonal antibody directed against the MMP cleavage site of OPN.
Conclusions
These findings show that MMP cleavage of OPN in AT occurs in obesity, thereby enhancing OPN's inflammatory and pro‐diabetic activity on adipocytes. Specifically targeting MMP‐cleaved OPN opens avenues for prevention and treatment of obesity‐induced type 2 diabetes.</abstract><cop>United States</cop><pub>Blackwell Publishing Ltd</pub><pmid>25776538</pmid><doi>10.1002/oby.21024</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Obesity (Silver Spring, Md.), 2015-04, Vol.23 (4), p.779-785 |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete; Wiley Online Library Free Content |
| subjects | Adipocytes Adipocytes - metabolism Adipose Tissue - metabolism Binding sites Cytokines Diabetes Gastrointestinal surgery Gene expression Humans Insulin Resistance Matrix Metalloproteinase 9 - metabolism Metabolism Obesity Obesity - immunology Obesity - physiopathology Obesity - prevention & control Osteopontin - metabolism Proteins Rodents Studies |
| title | Immunological blockade of adipocyte inflammation caused by increased matrix metalloproteinase‐cleaved osteopontin in obesity |
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