Tyk2 and Stat3 Regulate Brown Adipose Tissue Differentiation and Obesity
Identifieur interne : 001057 ( Ncbi/Merge ); précédent : 001056; suivant : 001058Tyk2 and Stat3 Regulate Brown Adipose Tissue Differentiation and Obesity
Auteurs : Marta Derecka [États-Unis] ; Agnieszka Gornicka [États-Unis] ; Sergei B. Koralov [États-Unis] ; Karol Szczepanek [États-Unis] ; Magdalena Morgan [États-Unis] ; Vidisha Raje [États-Unis] ; Jennifer Sisler [États-Unis] ; Qifang Zhang [États-Unis] ; Dennis Otero [États-Unis] ; Joanna Cichy [Pologne] ; Klaus Rajewsky [États-Unis] ; Kazuya Shimoda [Japon] ; Valeria Poli ; Birgit Strobl [Autriche] ; Sandra Pellegrini [France] ; Thurl E. Harris [États-Unis] ; Patrick Seale [États-Unis] ; Aaron P. Russell [Australie] ; Andrew J. Mcainch [Australie] ; Paul E. O Rien [Australie] ; Susanna R. Keller [États-Unis] ; Colleen M. Croniger [États-Unis] ; Tomasz Kordula [États-Unis] ; Andrew C. Larner [États-Unis]Source :
- Cell metabolism [ 1550-4131 ] ; 2012.
Abstract
Mice lacking the Jak tyrosine kinase member Tyk2 become progressively obese due to aberrant development of Myf5+ brown adipose tissue (BAT). Tyk2 RNA levels in BAT and skeletal muscle, which shares a common progenitor with BAT, are dramatically decreased in mice placed on a high fat diet and in obese humans. Expression of Tyk2 or the constitutively active form of the transcription factor Stat3 (CAStat3) restores differentiation in Tyk2−/− brown preadipocytes. Furthermore, Tyk2−/− mice expressing CAStat3 transgene in BAT also show improved BAT development, normal levels of insulin and significantly lower body weights. Stat3 binds to PRDM16, a master regulator of BAT differentiation, and enhances the stability of PRDM16 protein. These results define Tyk2 and Stat3 as critical determinants of brown fat-lineage and suggest that altered levels of Tyk2 are associated with obesity in both rodents and humans.
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DOI: 10.1016/j.cmet.2012.11.005
PubMed: 23217260
PubMed Central: 3522427
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Roux 75724 Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Department of Immunology, Institut Pasteur, 25, 28 rue du Docteur Roux 75724 Paris</wicri:regionArea><wicri:noRegion>75724 Paris</wicri:noRegion><wicri:noRegion>75724 Paris</wicri:noRegion></affiliation></author><author><name sortKey="Harris, Thurl E" sort="Harris, Thurl E" uniqKey="Harris T" first="Thurl E." last="Harris">Thurl E. 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Russell</name><affiliation wicri:level="1"><nlm:aff id="A13">Centre of Physical Activity and Nutrition (C-PAN) Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, 3125, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Centre of Physical Activity and Nutrition (C-PAN) Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, 3125</wicri:regionArea><wicri:noRegion>3125</wicri:noRegion></affiliation></author><author><name sortKey="Mcainch, Andrew J" sort="Mcainch, Andrew J" uniqKey="Mcainch A" first="Andrew J." last="Mcainch">Andrew J. Mcainch</name><affiliation wicri:level="1"><nlm:aff id="A14">Biomedical and Lifestyle Diseases (BioLED) Unit, School of Biomedical and Health Sciences, Victoria University, St Albans, 3021, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Biomedical and Lifestyle Diseases (BioLED) Unit, School of Biomedical and Health Sciences, Victoria University, St Albans, 3021</wicri:regionArea><wicri:noRegion>3021</wicri:noRegion></affiliation></author><author><name sortKey="O Rien, Paul E" sort="O Rien, Paul E" uniqKey="O Rien P" first="Paul E." last="O Rien">Paul E. O Rien</name><affiliation wicri:level="1"><nlm:aff id="A15">Centre for Obesity Research and Education (CORE), Monash University, The Alfred Hospital, Melbourne, 3004, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Centre for Obesity Research and Education (CORE), Monash University, The Alfred Hospital, Melbourne, 3004</wicri:regionArea><wicri:noRegion>3004</wicri:noRegion></affiliation></author><author><name sortKey="Keller, Susanna R" sort="Keller, Susanna R" uniqKey="Keller S" first="Susanna R." last="Keller">Susanna R. Keller</name><affiliation wicri:level="2"><nlm:aff id="A16">Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908</wicri:regionArea><placeName><region type="state">Virginie</region></placeName></affiliation></author><author><name sortKey="Croniger, Colleen M" sort="Croniger, Colleen M" uniqKey="Croniger C" first="Colleen M." last="Croniger">Colleen M. Croniger</name><affiliation wicri:level="2"><nlm:aff id="A17">Department of Nutrition, Case Western University School of Medicine Cleveland, OH 44106, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Nutrition, Case Western University School of Medicine Cleveland, OH 44106</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Kordula, Tomasz" sort="Kordula, Tomasz" uniqKey="Kordula T" first="Tomasz" last="Kordula">Tomasz Kordula</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298</wicri:regionArea><placeName><region type="state">Virginie</region></placeName></affiliation></author><author><name sortKey="Larner, Andrew C" sort="Larner, Andrew C" uniqKey="Larner A" first="Andrew C." last="Larner">Andrew C. 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Koralov</name><affiliation wicri:level="2"><nlm:aff id="A3">New York University Medical School, Department of Pathology, New York, NY 10016</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>New York University Medical School, Department of Pathology, New York</wicri:cityArea></affiliation></author><author><name sortKey="Szczepanek, Karol" sort="Szczepanek, Karol" uniqKey="Szczepanek K" first="Karol" last="Szczepanek">Karol Szczepanek</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298</wicri:regionArea><placeName><region type="state">Virginie</region></placeName></affiliation></author><author><name sortKey="Morgan, Magdalena" sort="Morgan, Magdalena" uniqKey="Morgan M" first="Magdalena" last="Morgan">Magdalena Morgan</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298</wicri:regionArea><placeName><region type="state">Virginie</region></placeName></affiliation></author><author><name sortKey="Raje, Vidisha" sort="Raje, Vidisha" uniqKey="Raje V" first="Vidisha" last="Raje">Vidisha Raje</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298</wicri:regionArea><placeName><region type="state">Virginie</region></placeName></affiliation></author><author><name sortKey="Sisler, Jennifer" sort="Sisler, Jennifer" uniqKey="Sisler J" first="Jennifer" last="Sisler">Jennifer Sisler</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298</wicri:regionArea><placeName><region type="state">Virginie</region></placeName></affiliation></author><author><name sortKey="Zhang, Qifang" sort="Zhang, Qifang" uniqKey="Zhang Q" first="Qifang" last="Zhang">Qifang Zhang</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298</wicri:regionArea><placeName><region type="state">Virginie</region></placeName></affiliation></author><author><name sortKey="Otero, Dennis" sort="Otero, Dennis" uniqKey="Otero D" first="Dennis" last="Otero">Dennis Otero</name><affiliation wicri:level="2"><nlm:aff id="A4">Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Cichy, Joanna" sort="Cichy, Joanna" uniqKey="Cichy J" first="Joanna" last="Cichy">Joanna Cichy</name><affiliation wicri:level="1"><nlm:aff id="A5">Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland</nlm:aff><country xml:lang="fr">Pologne</country><wicri:regionArea>Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow</wicri:regionArea><wicri:noRegion>Krakow</wicri:noRegion></affiliation></author><author><name sortKey="Rajewsky, Klaus" sort="Rajewsky, Klaus" uniqKey="Rajewsky K" first="Klaus" last="Rajewsky">Klaus Rajewsky</name><affiliation wicri:level="2"><nlm:aff id="A6">Program in Cellular and Molecular Medicine, Children Hospital, and Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Program in Cellular and Molecular Medicine, Children Hospital, and Immune Disease Institute, Harvard Medical School, Boston, MA 02115</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Shimoda, Kazuya" sort="Shimoda, Kazuya" uniqKey="Shimoda K" first="Kazuya" last="Shimoda">Kazuya Shimoda</name><affiliation wicri:level="1"><nlm:aff id="A7">Department of Gastroenterology and Hematology, Faculty of Medicine, Miyazaki University, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Gastroenterology and Hematology, Faculty of Medicine, Miyazaki University</wicri:regionArea><wicri:noRegion>Miyazaki University</wicri:noRegion></affiliation></author><author><name sortKey="Poli, Valeria" sort="Poli, Valeria" uniqKey="Poli V" first="Valeria" last="Poli">Valeria Poli</name><affiliation><nlm:aff id="A8">Department of Genetics, Biology and Biochemistry, Molecular Biotechnology Center University of Turin, Via Nizza 52, 10126 Torino Italy</nlm:aff><wicri:noCountry code="subfield">10126 Torino Italy</wicri:noCountry></affiliation></author><author><name sortKey="Strobl, Birgit" sort="Strobl, Birgit" uniqKey="Strobl B" first="Birgit" last="Strobl">Birgit Strobl</name><affiliation wicri:level="1"><nlm:aff id="A9">Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Austria</nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea>Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna</wicri:regionArea><wicri:noRegion>University of Veterinary Medicine Vienna</wicri:noRegion></affiliation></author><author><name sortKey="Pellegrini, Sandra" sort="Pellegrini, Sandra" uniqKey="Pellegrini S" first="Sandra" last="Pellegrini">Sandra Pellegrini</name><affiliation wicri:level="1"><nlm:aff id="A10">Department of Immunology, Institut Pasteur, 25, 28 rue du Docteur Roux 75724 Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Department of Immunology, Institut Pasteur, 25, 28 rue du Docteur Roux 75724 Paris</wicri:regionArea><wicri:noRegion>75724 Paris</wicri:noRegion><wicri:noRegion>75724 Paris</wicri:noRegion></affiliation></author><author><name sortKey="Harris, Thurl E" sort="Harris, Thurl E" uniqKey="Harris T" first="Thurl E." last="Harris">Thurl E. Harris</name><affiliation wicri:level="1"><nlm:aff id="A11">Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22903</wicri:regionArea><wicri:noRegion>22903</wicri:noRegion></affiliation></author><author><name sortKey="Seale, Patrick" sort="Seale, Patrick" uniqKey="Seale P" first="Patrick" last="Seale">Patrick Seale</name><affiliation wicri:level="1"><nlm:aff id="A12">Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104</wicri:regionArea><wicri:noRegion>19104</wicri:noRegion></affiliation></author><author><name sortKey="Russell, Aaron P" sort="Russell, Aaron P" uniqKey="Russell A" first="Aaron P." last="Russell">Aaron P. Russell</name><affiliation wicri:level="1"><nlm:aff id="A13">Centre of Physical Activity and Nutrition (C-PAN) Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, 3125, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Centre of Physical Activity and Nutrition (C-PAN) Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, 3125</wicri:regionArea><wicri:noRegion>3125</wicri:noRegion></affiliation></author><author><name sortKey="Mcainch, Andrew J" sort="Mcainch, Andrew J" uniqKey="Mcainch A" first="Andrew J." last="Mcainch">Andrew J. Mcainch</name><affiliation wicri:level="1"><nlm:aff id="A14">Biomedical and Lifestyle Diseases (BioLED) Unit, School of Biomedical and Health Sciences, Victoria University, St Albans, 3021, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Biomedical and Lifestyle Diseases (BioLED) Unit, School of Biomedical and Health Sciences, Victoria University, St Albans, 3021</wicri:regionArea><wicri:noRegion>3021</wicri:noRegion></affiliation></author><author><name sortKey="O Rien, Paul E" sort="O Rien, Paul E" uniqKey="O Rien P" first="Paul E." last="O Rien">Paul E. O Rien</name><affiliation wicri:level="1"><nlm:aff id="A15">Centre for Obesity Research and Education (CORE), Monash University, The Alfred Hospital, Melbourne, 3004, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Centre for Obesity Research and Education (CORE), Monash University, The Alfred Hospital, Melbourne, 3004</wicri:regionArea><wicri:noRegion>3004</wicri:noRegion></affiliation></author><author><name sortKey="Keller, Susanna R" sort="Keller, Susanna R" uniqKey="Keller S" first="Susanna R." last="Keller">Susanna R. Keller</name><affiliation wicri:level="2"><nlm:aff id="A16">Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908</wicri:regionArea><placeName><region type="state">Virginie</region></placeName></affiliation></author><author><name sortKey="Croniger, Colleen M" sort="Croniger, Colleen M" uniqKey="Croniger C" first="Colleen M." last="Croniger">Colleen M. Croniger</name><affiliation wicri:level="2"><nlm:aff id="A17">Department of Nutrition, Case Western University School of Medicine Cleveland, OH 44106, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Nutrition, Case Western University School of Medicine Cleveland, OH 44106</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Kordula, Tomasz" sort="Kordula, Tomasz" uniqKey="Kordula T" first="Tomasz" last="Kordula">Tomasz Kordula</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298</wicri:regionArea><placeName><region type="state">Virginie</region></placeName></affiliation></author><author><name sortKey="Larner, Andrew C" sort="Larner, Andrew C" uniqKey="Larner A" first="Andrew C." last="Larner">Andrew C. Larner</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298</wicri:regionArea><placeName><region type="state">Virginie</region></placeName></affiliation></author></analytic><series><title level="j">Cell metabolism</title><idno type="ISSN">1550-4131</idno><idno type="eISSN">1932-7420</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P2">Mice lacking the Jak tyrosine kinase member Tyk2 become progressively obese due to aberrant development of Myf5+ brown adipose tissue (BAT). Tyk2 RNA levels in BAT and skeletal muscle, which shares a common progenitor with BAT, are dramatically decreased in mice placed on a high fat diet and in obese humans. Expression of Tyk2 or the constitutively active form of the transcription factor Stat3 (CAStat3) restores differentiation in Tyk2−/− brown preadipocytes. Furthermore, Tyk2−/− mice expressing CAStat3 transgene in BAT also show improved BAT development, normal levels of insulin and significantly lower body weights. Stat3 binds to PRDM16, a master regulator of BAT differentiation, and enhances the stability of PRDM16 protein. These results define Tyk2 and Stat3 as critical determinants of brown fat-lineage and suggest that altered levels of Tyk2 are associated with obesity in both rodents and humans.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">101233170</journal-id><journal-id journal-id-type="pubmed-jr-id">32527</journal-id><journal-id journal-id-type="nlm-ta">Cell Metab</journal-id><journal-id journal-id-type="iso-abbrev">Cell Metab.</journal-id><journal-title-group><journal-title>Cell metabolism</journal-title></journal-title-group><issn pub-type="ppub">1550-4131</issn><issn pub-type="epub">1932-7420</issn></journal-meta><article-meta><article-id pub-id-type="pmid">23217260</article-id><article-id pub-id-type="pmc">3522427</article-id><article-id pub-id-type="doi">10.1016/j.cmet.2012.11.005</article-id><article-id pub-id-type="manuscript">NIHMS422731</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Tyk2 and Stat3 Regulate Brown Adipose Tissue Differentiation and Obesity</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Derecka</surname><given-names>Marta</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Gornicka</surname><given-names>Agnieszka</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Koralov</surname><given-names>Sergei B.</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Szczepanek</surname><given-names>Karol</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Morgan</surname><given-names>Magdalena</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Raje</surname><given-names>Vidisha</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Sisler</surname><given-names>Jennifer</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Qifang</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Otero</surname><given-names>Dennis</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Cichy</surname><given-names>Joanna</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Rajewsky</surname><given-names>Klaus</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Shimoda</surname><given-names>Kazuya</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Poli</surname><given-names>Valeria</given-names></name><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>Strobl</surname><given-names>Birgit</given-names></name><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Pellegrini</surname><given-names>Sandra</given-names></name><xref ref-type="aff" rid="A10">10</xref></contrib><contrib contrib-type="author"><name><surname>Harris</surname><given-names>Thurl E.</given-names></name><xref ref-type="aff" rid="A11">11</xref></contrib><contrib contrib-type="author"><name><surname>Seale</surname><given-names>Patrick</given-names></name><xref ref-type="aff" rid="A12">12</xref></contrib><contrib contrib-type="author"><name><surname>Russell</surname><given-names>Aaron P.</given-names></name><xref ref-type="aff" rid="A13">13</xref></contrib><contrib contrib-type="author"><name><surname>McAinch</surname><given-names>Andrew J.</given-names></name><xref ref-type="aff" rid="A14">14</xref></contrib><contrib contrib-type="author"><name><surname>O’Brien</surname><given-names>Paul E.</given-names></name><xref ref-type="aff" rid="A15">15</xref></contrib><contrib contrib-type="author"><name><surname>Keller</surname><given-names>Susanna R.</given-names></name><xref ref-type="aff" rid="A16">16</xref></contrib><contrib contrib-type="author"><name><surname>Croniger</surname><given-names>Colleen M.</given-names></name><xref ref-type="aff" rid="A17">17</xref></contrib><contrib contrib-type="author"><name><surname>Kordula</surname><given-names>Tomasz</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Larner</surname><given-names>Andrew C.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref rid="FN1" ref-type="author-notes">18</xref></contrib></contrib-group><aff id="A1"><label>1</label>Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA</aff><aff id="A2"><label>2</label>Department of Immunology Cleveland Clinic Foundation, Cleveland, OH 44195, USA</aff><aff id="A3"><label>3</label>New York University Medical School, Department of Pathology, New York, NY 10016</aff><aff id="A4"><label>4</label>Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA</aff><aff id="A5"><label>5</label>Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland</aff><aff id="A6"><label>6</label>Program in Cellular and Molecular Medicine, Children Hospital, and Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA</aff><aff id="A7"><label>7</label>Department of Gastroenterology and Hematology, Faculty of Medicine, Miyazaki University, Japan</aff><aff id="A8"><label>8</label>Department of Genetics, Biology and Biochemistry, Molecular Biotechnology Center University of Turin, Via Nizza 52, 10126 Torino Italy</aff><aff id="A9"><label>9</label>Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Austria</aff><aff id="A10"><label>10</label>Department of Immunology, Institut Pasteur, 25, 28 rue du Docteur Roux 75724 Paris, France</aff><aff id="A11"><label>11</label>Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA</aff><aff id="A12"><label>12</label>Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA</aff><aff id="A13"><label>13</label>Centre of Physical Activity and Nutrition (C-PAN) Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, 3125, Australia</aff><aff id="A14"><label>14</label>Biomedical and Lifestyle Diseases (BioLED) Unit, School of Biomedical and Health Sciences, Victoria University, St Albans, 3021, Australia</aff><aff id="A15"><label>15</label>Centre for Obesity Research and Education (CORE), Monash University, The Alfred Hospital, Melbourne, 3004, Australia</aff><aff id="A16"><label>16</label>Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA</aff><aff id="A17"><label>17</label>Department of Nutrition, Case Western University School of Medicine Cleveland, OH 44106, USA</aff><author-notes><corresp id="FN1"><label>18</label>To whom correspondence should be addressed. Andrew Larner, Dept. of Biochemistry and Molecular Biology, VCU School of Medicine, MMRB, Rm 2050, 1220 East Broad St. Richmond, VA 23298, Tel. (804) 828-2903; Fax: (804) 827-1657; <email>alarner@vcu.ed</email></corresp></author-notes><pub-date pub-type="nihms-submitted"><day>28</day><month>11</month><year>2012</year></pub-date><pub-date pub-type="ppub"><day>5</day><month>12</month><year>2012</year></pub-date><pub-date pub-type="pmc-release"><day>05</day><month>12</month><year>2013</year></pub-date><volume>16</volume><issue>6</issue><fpage>814</fpage><lpage>824</lpage><permissions><copyright-statement>© 2012 Elsevier Inc. All rights reserved.</copyright-statement><copyright-year>2012</copyright-year></permissions><abstract><p id="P2">Mice lacking the Jak tyrosine kinase member Tyk2 become progressively obese due to aberrant development of Myf5+ brown adipose tissue (BAT). Tyk2 RNA levels in BAT and skeletal muscle, which shares a common progenitor with BAT, are dramatically decreased in mice placed on a high fat diet and in obese humans. Expression of Tyk2 or the constitutively active form of the transcription factor Stat3 (CAStat3) restores differentiation in Tyk2−/− brown preadipocytes. Furthermore, Tyk2−/− mice expressing CAStat3 transgene in BAT also show improved BAT development, normal levels of insulin and significantly lower body weights. Stat3 binds to PRDM16, a master regulator of BAT differentiation, and enhances the stability of PRDM16 protein. These results define Tyk2 and Stat3 as critical determinants of brown fat-lineage and suggest that altered levels of Tyk2 are associated with obesity in both rodents and humans.</p></abstract><funding-group><award-group><funding-source country="United States">National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID</funding-source><award-id>R21 AI088487 || AI</award-id></award-group><award-group><funding-source country="United States">National Institute of General Medical Sciences : NIGMS</funding-source><award-id>R01 GM101677 || GM</award-id></award-group><award-group><funding-source country="United States">National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID</funding-source><award-id>R01 AI059710 || AI</award-id></award-group></funding-group></article-meta></front></pmc><affiliations><list><country><li>Australie</li><li>Autriche</li><li>France</li><li>Japon</li><li>Pologne</li><li>États-Unis</li></country><region><li>Californie</li><li>Massachusetts</li><li>Ohio</li><li>Virginie</li><li>État de New York</li></region></list><tree><noCountry><name sortKey="Poli, Valeria" sort="Poli, Valeria" uniqKey="Poli V" first="Valeria" last="Poli">Valeria Poli</name></noCountry><country name="États-Unis"><region name="Virginie"><name sortKey="Derecka, Marta" sort="Derecka, Marta" uniqKey="Derecka M" first="Marta" last="Derecka">Marta Derecka</name></region><name sortKey="Croniger, Colleen M" sort="Croniger, Colleen M" uniqKey="Croniger C" first="Colleen M." last="Croniger">Colleen M. Croniger</name><name sortKey="Gornicka, Agnieszka" sort="Gornicka, Agnieszka" uniqKey="Gornicka A" first="Agnieszka" last="Gornicka">Agnieszka Gornicka</name><name sortKey="Harris, Thurl E" sort="Harris, Thurl E" uniqKey="Harris T" first="Thurl E." last="Harris">Thurl E. Harris</name><name sortKey="Keller, Susanna R" sort="Keller, Susanna R" uniqKey="Keller S" first="Susanna R." last="Keller">Susanna R. Keller</name><name sortKey="Koralov, Sergei B" sort="Koralov, Sergei B" uniqKey="Koralov S" first="Sergei B." last="Koralov">Sergei B. Koralov</name><name sortKey="Kordula, Tomasz" sort="Kordula, Tomasz" uniqKey="Kordula T" first="Tomasz" last="Kordula">Tomasz Kordula</name><name sortKey="Larner, Andrew C" sort="Larner, Andrew C" uniqKey="Larner A" first="Andrew C." last="Larner">Andrew C. Larner</name><name sortKey="Morgan, Magdalena" sort="Morgan, Magdalena" uniqKey="Morgan M" first="Magdalena" last="Morgan">Magdalena Morgan</name><name sortKey="Otero, Dennis" sort="Otero, Dennis" uniqKey="Otero D" first="Dennis" last="Otero">Dennis Otero</name><name sortKey="Raje, Vidisha" sort="Raje, Vidisha" uniqKey="Raje V" first="Vidisha" last="Raje">Vidisha Raje</name><name sortKey="Rajewsky, Klaus" sort="Rajewsky, Klaus" uniqKey="Rajewsky K" first="Klaus" last="Rajewsky">Klaus Rajewsky</name><name sortKey="Seale, Patrick" sort="Seale, Patrick" uniqKey="Seale P" first="Patrick" last="Seale">Patrick Seale</name><name sortKey="Sisler, Jennifer" sort="Sisler, Jennifer" uniqKey="Sisler J" first="Jennifer" last="Sisler">Jennifer Sisler</name><name sortKey="Szczepanek, Karol" sort="Szczepanek, Karol" uniqKey="Szczepanek K" first="Karol" last="Szczepanek">Karol Szczepanek</name><name sortKey="Zhang, Qifang" sort="Zhang, Qifang" uniqKey="Zhang Q" first="Qifang" last="Zhang">Qifang Zhang</name></country><country name="Pologne"><noRegion><name sortKey="Cichy, Joanna" sort="Cichy, Joanna" uniqKey="Cichy J" first="Joanna" last="Cichy">Joanna Cichy</name></noRegion></country><country name="Japon"><noRegion><name sortKey="Shimoda, Kazuya" sort="Shimoda, Kazuya" uniqKey="Shimoda K" first="Kazuya" last="Shimoda">Kazuya Shimoda</name></noRegion></country><country name="Autriche"><noRegion><name sortKey="Strobl, Birgit" sort="Strobl, Birgit" uniqKey="Strobl B" first="Birgit" last="Strobl">Birgit Strobl</name></noRegion></country><country name="France"><noRegion><name sortKey="Pellegrini, Sandra" sort="Pellegrini, Sandra" uniqKey="Pellegrini S" first="Sandra" last="Pellegrini">Sandra Pellegrini</name></noRegion></country><country name="Australie"><noRegion><name sortKey="Russell, Aaron P" sort="Russell, Aaron P" uniqKey="Russell A" first="Aaron P." last="Russell">Aaron P. Russell</name></noRegion><name sortKey="Mcainch, Andrew J" sort="Mcainch, Andrew J" uniqKey="Mcainch A" first="Andrew J." last="Mcainch">Andrew J. Mcainch</name><name sortKey="O Rien, Paul E" sort="O Rien, Paul E" uniqKey="O Rien P" first="Paul E." last="O Rien">Paul E. O Rien</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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