PGRN is a Key Adipokine Mediating High Fat Diet-Induced Insulin Resistance and Obesity through IL-6 in Adipose Tissue
Adipose tissue secretes adipokines that mediate insulin resistance, a characteristic feature of obesity and type 2 diabetes. By differential proteome analysis of cellular models of insulin resistance, we identified progranulin (PGRN) as an adipokine induced by TNF-α and dexamethasone. PGRN in blood...
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| Veröffentlicht in: | Cell metabolism 2012-01, Vol.15 (1), p.38-50 |
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| creator | Matsubara, Toshiya Mita, Ayako Minami, Kohtaro Hosooka, Tetsuya Kitazawa, Sohei Takahashi, Kenichi Tamori, Yoshikazu Yokoi, Norihide Watanabe, Makoto Matsuo, Ei-ichi Nishimura, Osamu Seino, Susumu |
| description | Adipose tissue secretes adipokines that mediate insulin resistance, a characteristic feature of obesity and type 2 diabetes. By differential proteome analysis of cellular models of insulin resistance, we identified progranulin (PGRN) as an adipokine induced by TNF-α and dexamethasone. PGRN in blood and adipose tissues was markedly increased in obese mouse models and was normalized with treatment of pioglitazone, an insulin-sensitizing agent. Ablation of PGRN (Grn−/−) prevented mice from high fat diet (HFD)-induced insulin resistance, adipocyte hypertrophy, and obesity. Grn deficiency blocked elevation of IL-6, an inflammatory cytokine, induced by HFD in blood and adipose tissues. Insulin resistance induced by chronic administration of PGRN was suppressed by neutralizing IL-6 in vivo. Thus, PGRN is a key adipokine that mediates HFD-induced insulin resistance and obesity through production of IL-6 in adipose tissue, and may be a promising therapeutic target for obesity.
► PGRN is a key adipokine identified by differential proteome analysis ► PGRN is associated with insulin resistance both in vitro and in vivo ► PGRN mediates systemic insulin resistance by induction of IL-6 in adipose tissues ► Ablation of PGRN prevents HFD-induced insulin resistance and obesity |
| doi_str_mv | 10.1016/j.cmet.2011.12.002 |
| format | Article |
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► PGRN is a key adipokine identified by differential proteome analysis ► PGRN is associated with insulin resistance both in vitro and in vivo ► PGRN mediates systemic insulin resistance by induction of IL-6 in adipose tissues ► Ablation of PGRN prevents HFD-induced insulin resistance and obesity</description><identifier>ISSN: 1550-4131</identifier><identifier>EISSN: 1932-7420</identifier><identifier>DOI: 10.1016/j.cmet.2011.12.002</identifier><identifier>PMID: 22225875</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>3T3-L1 Cells ; Adipokines - metabolism ; Adipose Tissue - drug effects ; Adipose Tissue - metabolism ; Animals ; Dexamethasone - pharmacology ; Diet, High-Fat ; Insulin Resistance ; Intercellular Signaling Peptides and Proteins - genetics ; Intercellular Signaling Peptides and Proteins - metabolism ; Intercellular Signaling Peptides and Proteins - pharmacology ; Interleukin-6 - metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Obesity - blood ; Obesity - metabolism ; Obesity - prevention & control ; Recombinant Proteins - genetics ; Recombinant Proteins - metabolism ; Recombinant Proteins - pharmacology ; Thiazolidinediones - pharmacology ; Tumor Necrosis Factor-alpha - pharmacology</subject><ispartof>Cell metabolism, 2012-01, Vol.15 (1), p.38-50</ispartof><rights>2012 Elsevier Inc.</rights><rights>Copyright © 2012 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c432t-2089bb0a2ed2c1332e20ebbd9b4ba5f21b59f0d29b419038b96f52e18dc4947f3</citedby><cites>FETCH-LOGICAL-c432t-2089bb0a2ed2c1332e20ebbd9b4ba5f21b59f0d29b419038b96f52e18dc4947f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1550413111004608$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22225875$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Matsubara, Toshiya</creatorcontrib><creatorcontrib>Mita, Ayako</creatorcontrib><creatorcontrib>Minami, Kohtaro</creatorcontrib><creatorcontrib>Hosooka, Tetsuya</creatorcontrib><creatorcontrib>Kitazawa, Sohei</creatorcontrib><creatorcontrib>Takahashi, Kenichi</creatorcontrib><creatorcontrib>Tamori, Yoshikazu</creatorcontrib><creatorcontrib>Yokoi, Norihide</creatorcontrib><creatorcontrib>Watanabe, Makoto</creatorcontrib><creatorcontrib>Matsuo, Ei-ichi</creatorcontrib><creatorcontrib>Nishimura, Osamu</creatorcontrib><creatorcontrib>Seino, Susumu</creatorcontrib><title>PGRN is a Key Adipokine Mediating High Fat Diet-Induced Insulin Resistance and Obesity through IL-6 in Adipose Tissue</title><title>Cell metabolism</title><addtitle>Cell Metab</addtitle><description>Adipose tissue secretes adipokines that mediate insulin resistance, a characteristic feature of obesity and type 2 diabetes. By differential proteome analysis of cellular models of insulin resistance, we identified progranulin (PGRN) as an adipokine induced by TNF-α and dexamethasone. PGRN in blood and adipose tissues was markedly increased in obese mouse models and was normalized with treatment of pioglitazone, an insulin-sensitizing agent. Ablation of PGRN (Grn−/−) prevented mice from high fat diet (HFD)-induced insulin resistance, adipocyte hypertrophy, and obesity. Grn deficiency blocked elevation of IL-6, an inflammatory cytokine, induced by HFD in blood and adipose tissues. Insulin resistance induced by chronic administration of PGRN was suppressed by neutralizing IL-6 in vivo. Thus, PGRN is a key adipokine that mediates HFD-induced insulin resistance and obesity through production of IL-6 in adipose tissue, and may be a promising therapeutic target for obesity.
► PGRN is a key adipokine identified by differential proteome analysis ► PGRN is associated with insulin resistance both in vitro and in vivo ► PGRN mediates systemic insulin resistance by induction of IL-6 in adipose tissues ► Ablation of PGRN prevents HFD-induced insulin resistance and obesity</description><subject>3T3-L1 Cells</subject><subject>Adipokines - metabolism</subject><subject>Adipose Tissue - drug effects</subject><subject>Adipose Tissue - metabolism</subject><subject>Animals</subject><subject>Dexamethasone - pharmacology</subject><subject>Diet, High-Fat</subject><subject>Insulin Resistance</subject><subject>Intercellular Signaling Peptides and Proteins - genetics</subject><subject>Intercellular Signaling Peptides and Proteins - metabolism</subject><subject>Intercellular Signaling Peptides and Proteins - pharmacology</subject><subject>Interleukin-6 - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Obese</subject><subject>Obesity - blood</subject><subject>Obesity - metabolism</subject><subject>Obesity - prevention & control</subject><subject>Recombinant Proteins - genetics</subject><subject>Recombinant Proteins - metabolism</subject><subject>Recombinant Proteins - pharmacology</subject><subject>Thiazolidinediones - pharmacology</subject><subject>Tumor Necrosis Factor-alpha - pharmacology</subject><issn>1550-4131</issn><issn>1932-7420</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUtPHDEQhK0oEa_wB3KIfAuXGez2eHYscUE8V2xChMjZ8qMHvOzOLGMP0v57vCzhSF-6W_qqDlWE_OCs5IzXx_PSLTGVwDgvOZSMwReyx5WAYlIB-5pvKVlRccF3yX6Mc8ZELZTYIbuQRzYTuUfGv1d3f2iI1NAbXNNTH1b9U-iQ_kYfTArdA70OD4_00iR6HjAV086PDj2ddnFchI7eYQwxmc4hNZ2ntzb_aU3T49CPWTedFTXN2JtxRHofYhzxO_nWmkXEw_d9QP5dXtyfXRez26vp2emscJWAVABrlLXMAHpwXAhAYGitV7ayRrbArVQt85B_rphorKpbCcgb7ypVTVpxQH5tfVdD_zxiTHoZosPFwnTYj1ErLlmWSpnJo09JXsEk59c0dUZhi7qhj3HAVq-GsDTDWnOmN8Xoud4UozfFaA46F5NFP9_9R7tE_yH530QGTrYA5jxeAg46uoA5Vh8GdEn7Pnzm_womiZ1R</recordid><startdate>20120104</startdate><enddate>20120104</enddate><creator>Matsubara, Toshiya</creator><creator>Mita, Ayako</creator><creator>Minami, Kohtaro</creator><creator>Hosooka, Tetsuya</creator><creator>Kitazawa, Sohei</creator><creator>Takahashi, Kenichi</creator><creator>Tamori, Yoshikazu</creator><creator>Yokoi, Norihide</creator><creator>Watanabe, Makoto</creator><creator>Matsuo, Ei-ichi</creator><creator>Nishimura, Osamu</creator><creator>Seino, Susumu</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</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>7TS</scope><scope>7X8</scope></search><sort><creationdate>20120104</creationdate><title>PGRN is a Key Adipokine Mediating High Fat Diet-Induced Insulin Resistance and Obesity through IL-6 in Adipose Tissue</title><author>Matsubara, Toshiya ; Mita, Ayako ; Minami, Kohtaro ; Hosooka, Tetsuya ; Kitazawa, Sohei ; Takahashi, Kenichi ; Tamori, Yoshikazu ; Yokoi, Norihide ; Watanabe, Makoto ; Matsuo, Ei-ichi ; Nishimura, Osamu ; Seino, Susumu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c432t-2089bb0a2ed2c1332e20ebbd9b4ba5f21b59f0d29b419038b96f52e18dc4947f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>3T3-L1 Cells</topic><topic>Adipokines - metabolism</topic><topic>Adipose Tissue - drug effects</topic><topic>Adipose Tissue - metabolism</topic><topic>Animals</topic><topic>Dexamethasone - pharmacology</topic><topic>Diet, High-Fat</topic><topic>Insulin Resistance</topic><topic>Intercellular Signaling Peptides and Proteins - genetics</topic><topic>Intercellular Signaling Peptides and Proteins - metabolism</topic><topic>Intercellular Signaling Peptides and Proteins - pharmacology</topic><topic>Interleukin-6 - metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Obese</topic><topic>Obesity - blood</topic><topic>Obesity - metabolism</topic><topic>Obesity - prevention & control</topic><topic>Recombinant Proteins - genetics</topic><topic>Recombinant Proteins - metabolism</topic><topic>Recombinant Proteins - pharmacology</topic><topic>Thiazolidinediones - pharmacology</topic><topic>Tumor Necrosis Factor-alpha - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Matsubara, Toshiya</creatorcontrib><creatorcontrib>Mita, Ayako</creatorcontrib><creatorcontrib>Minami, Kohtaro</creatorcontrib><creatorcontrib>Hosooka, Tetsuya</creatorcontrib><creatorcontrib>Kitazawa, Sohei</creatorcontrib><creatorcontrib>Takahashi, Kenichi</creatorcontrib><creatorcontrib>Tamori, Yoshikazu</creatorcontrib><creatorcontrib>Yokoi, Norihide</creatorcontrib><creatorcontrib>Watanabe, Makoto</creatorcontrib><creatorcontrib>Matsuo, Ei-ichi</creatorcontrib><creatorcontrib>Nishimura, Osamu</creatorcontrib><creatorcontrib>Seino, Susumu</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Physical Education Index</collection><collection>MEDLINE - Academic</collection><jtitle>Cell metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Matsubara, Toshiya</au><au>Mita, Ayako</au><au>Minami, Kohtaro</au><au>Hosooka, Tetsuya</au><au>Kitazawa, Sohei</au><au>Takahashi, Kenichi</au><au>Tamori, Yoshikazu</au><au>Yokoi, Norihide</au><au>Watanabe, Makoto</au><au>Matsuo, Ei-ichi</au><au>Nishimura, Osamu</au><au>Seino, Susumu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PGRN is a Key Adipokine Mediating High Fat Diet-Induced Insulin Resistance and Obesity through IL-6 in Adipose Tissue</atitle><jtitle>Cell metabolism</jtitle><addtitle>Cell Metab</addtitle><date>2012-01-04</date><risdate>2012</risdate><volume>15</volume><issue>1</issue><spage>38</spage><epage>50</epage><pages>38-50</pages><issn>1550-4131</issn><eissn>1932-7420</eissn><abstract>Adipose tissue secretes adipokines that mediate insulin resistance, a characteristic feature of obesity and type 2 diabetes. By differential proteome analysis of cellular models of insulin resistance, we identified progranulin (PGRN) as an adipokine induced by TNF-α and dexamethasone. PGRN in blood and adipose tissues was markedly increased in obese mouse models and was normalized with treatment of pioglitazone, an insulin-sensitizing agent. Ablation of PGRN (Grn−/−) prevented mice from high fat diet (HFD)-induced insulin resistance, adipocyte hypertrophy, and obesity. Grn deficiency blocked elevation of IL-6, an inflammatory cytokine, induced by HFD in blood and adipose tissues. Insulin resistance induced by chronic administration of PGRN was suppressed by neutralizing IL-6 in vivo. Thus, PGRN is a key adipokine that mediates HFD-induced insulin resistance and obesity through production of IL-6 in adipose tissue, and may be a promising therapeutic target for obesity.
► PGRN is a key adipokine identified by differential proteome analysis ► PGRN is associated with insulin resistance both in vitro and in vivo ► PGRN mediates systemic insulin resistance by induction of IL-6 in adipose tissues ► Ablation of PGRN prevents HFD-induced insulin resistance and obesity</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>22225875</pmid><doi>10.1016/j.cmet.2011.12.002</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 3T3-L1 Cells Adipokines - metabolism Adipose Tissue - drug effects Adipose Tissue - metabolism Animals Dexamethasone - pharmacology Diet, High-Fat Insulin Resistance Intercellular Signaling Peptides and Proteins - genetics Intercellular Signaling Peptides and Proteins - metabolism Intercellular Signaling Peptides and Proteins - pharmacology Interleukin-6 - metabolism Male Mice Mice, Inbred C57BL Mice, Obese Obesity - blood Obesity - metabolism Obesity - prevention & control Recombinant Proteins - genetics Recombinant Proteins - metabolism Recombinant Proteins - pharmacology Thiazolidinediones - pharmacology Tumor Necrosis Factor-alpha - pharmacology |
| title | PGRN is a Key Adipokine Mediating High Fat Diet-Induced Insulin Resistance and Obesity through IL-6 in Adipose Tissue |
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