GRP94 regulates M1 macrophage polarization and insulin resistance
Macrophage polarization contributes to obesity-induced insulin resistance. Glucose-regulated protein 94 (GRP94) is an endoplasmic reticulum (ER) chaperone specialized for folding and quality control of secreted and membrane proteins. To determine the role of GRP94 in macrophage polarization and insu...
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| Veröffentlicht in: | American journal of physiology: endocrinology and metabolism 2020-06, Vol.318 (6), p.E1004-E1013 |
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| container_title | American journal of physiology: endocrinology and metabolism |
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| creator | Song, Lili Kim, Do-Sung Gou, Wenyu Wang, Jingjing Wang, Ping Wei, Zhiguo Liu, Bei Li, Zihai Gou, Kemian Wang, Hongjun |
| description | Macrophage polarization contributes to obesity-induced insulin resistance. Glucose-regulated protein 94 (GRP94) is an endoplasmic reticulum (ER) chaperone specialized for folding and quality control of secreted and membrane proteins. To determine the role of GRP94 in macrophage polarization and insulin resistance, macrophage-specific GRP94 conditional knockout (KO) mice were challenged with a high-fat diet (HFD). Glucose tolerance, insulin sensitivity, and macrophage composition were compared with control mice. KO mice showed better glucose tolerance and increased insulin sensitivity. Adipose tissues from HFD-KO mice contained lower numbers of M1 macrophages, with lower expression of M1 macrophage markers, than wild-type (WT) mice. In vitro, WT adipocytes cocultured with KO macrophages retained insulin sensitivity, whereas those cultured with WT macrophages did not. In addition, compared with WT bone marrow-derived macrophages (BMDMs), BMDMs from GRP94 KO mice exhibited lower expression of M1 macrophage marker genes following stimulation with LPS or IFN-γ, and exhibited partially increased expression of M2 macrophage marker genes following stimulation with interleukin-4. These findings identify GRP94 as a novel regulator of M1 macrophage polarization and insulin resistance and inflammation. |
| doi_str_mv | 10.1152/AJPENDO.00542.2019 |
| format | Article |
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Glucose-regulated protein 94 (GRP94) is an endoplasmic reticulum (ER) chaperone specialized for folding and quality control of secreted and membrane proteins. To determine the role of GRP94 in macrophage polarization and insulin resistance, macrophage-specific GRP94 conditional knockout (KO) mice were challenged with a high-fat diet (HFD). Glucose tolerance, insulin sensitivity, and macrophage composition were compared with control mice. KO mice showed better glucose tolerance and increased insulin sensitivity. Adipose tissues from HFD-KO mice contained lower numbers of M1 macrophages, with lower expression of M1 macrophage markers, than wild-type (WT) mice. In vitro, WT adipocytes cocultured with KO macrophages retained insulin sensitivity, whereas those cultured with WT macrophages did not. In addition, compared with WT bone marrow-derived macrophages (BMDMs), BMDMs from GRP94 KO mice exhibited lower expression of M1 macrophage marker genes following stimulation with LPS or IFN-γ, and exhibited partially increased expression of M2 macrophage marker genes following stimulation with interleukin-4. These findings identify GRP94 as a novel regulator of M1 macrophage polarization and insulin resistance and inflammation.</description><identifier>ISSN: 0193-1849</identifier><identifier>EISSN: 1522-1555</identifier><identifier>DOI: 10.1152/AJPENDO.00542.2019</identifier><identifier>PMID: 32208002</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>3T3-L1 Cells ; Adipocytes - metabolism ; Animals ; Coculture Techniques ; Cytokines - genetics ; Cytokines - immunology ; Diet, High-Fat ; Glucose Tolerance Test ; Inflammation - genetics ; Inflammation - immunology ; Insulin Resistance - genetics ; Insulin Resistance - immunology ; Interferon-gamma - pharmacology ; Lipopolysaccharides - pharmacology ; Macrophage Activation - genetics ; Macrophage Activation - immunology ; Macrophages - drug effects ; Macrophages - immunology ; Membrane Glycoproteins - genetics ; Membrane Glycoproteins - immunology ; Mice ; Mice, Knockout ; Obesity - genetics ; Obesity - immunology ; Obesity - metabolism ; RNA, Messenger - metabolism</subject><ispartof>American journal of physiology: endocrinology and metabolism, 2020-06, Vol.318 (6), p.E1004-E1013</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c402t-d15da88267e765d5fdf553fc3c8975f81998987dd3069abb3c4b142b2745bfd23</citedby><cites>FETCH-LOGICAL-c402t-d15da88267e765d5fdf553fc3c8975f81998987dd3069abb3c4b142b2745bfd23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3039,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32208002$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Song, Lili</creatorcontrib><creatorcontrib>Kim, Do-Sung</creatorcontrib><creatorcontrib>Gou, Wenyu</creatorcontrib><creatorcontrib>Wang, Jingjing</creatorcontrib><creatorcontrib>Wang, Ping</creatorcontrib><creatorcontrib>Wei, Zhiguo</creatorcontrib><creatorcontrib>Liu, Bei</creatorcontrib><creatorcontrib>Li, Zihai</creatorcontrib><creatorcontrib>Gou, Kemian</creatorcontrib><creatorcontrib>Wang, Hongjun</creatorcontrib><title>GRP94 regulates M1 macrophage polarization and insulin resistance</title><title>American journal of physiology: endocrinology and metabolism</title><addtitle>Am J Physiol Endocrinol Metab</addtitle><description>Macrophage polarization contributes to obesity-induced insulin resistance. Glucose-regulated protein 94 (GRP94) is an endoplasmic reticulum (ER) chaperone specialized for folding and quality control of secreted and membrane proteins. To determine the role of GRP94 in macrophage polarization and insulin resistance, macrophage-specific GRP94 conditional knockout (KO) mice were challenged with a high-fat diet (HFD). Glucose tolerance, insulin sensitivity, and macrophage composition were compared with control mice. KO mice showed better glucose tolerance and increased insulin sensitivity. Adipose tissues from HFD-KO mice contained lower numbers of M1 macrophages, with lower expression of M1 macrophage markers, than wild-type (WT) mice. In vitro, WT adipocytes cocultured with KO macrophages retained insulin sensitivity, whereas those cultured with WT macrophages did not. In addition, compared with WT bone marrow-derived macrophages (BMDMs), BMDMs from GRP94 KO mice exhibited lower expression of M1 macrophage marker genes following stimulation with LPS or IFN-γ, and exhibited partially increased expression of M2 macrophage marker genes following stimulation with interleukin-4. These findings identify GRP94 as a novel regulator of M1 macrophage polarization and insulin resistance and inflammation.</description><subject>3T3-L1 Cells</subject><subject>Adipocytes - metabolism</subject><subject>Animals</subject><subject>Coculture Techniques</subject><subject>Cytokines - genetics</subject><subject>Cytokines - immunology</subject><subject>Diet, High-Fat</subject><subject>Glucose Tolerance Test</subject><subject>Inflammation - genetics</subject><subject>Inflammation - immunology</subject><subject>Insulin Resistance - genetics</subject><subject>Insulin Resistance - immunology</subject><subject>Interferon-gamma - pharmacology</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>Macrophage Activation - genetics</subject><subject>Macrophage Activation - immunology</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - immunology</subject><subject>Membrane Glycoproteins - genetics</subject><subject>Membrane Glycoproteins - immunology</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Obesity - genetics</subject><subject>Obesity - immunology</subject><subject>Obesity - metabolism</subject><subject>RNA, Messenger - metabolism</subject><issn>0193-1849</issn><issn>1522-1555</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkF1PwjAUhhujEUT_gBdml94M-7Gu7Y0JUUQNCjF63XRrByWjm-1mor_eIUj06iTn_TgnDwDnCA4Rovhq9DgfP9_OhhDSBA8xROIA9DsBx4hSegj63YbEiCeiB05CWEEIWec8Bj2CMeQQ4j4YTV7mIom8WbSlakyInlC0Vrmv6qVamKiuSuXtl2ps5SLldGRdaEvrukCwoVEuN6fgqFBlMGe7OQBvd-PXm_t4Ops83IymcZ5A3MQaUa04xykzLKWaFrqglBQ5yblgtOBICC4405rAVKgsI3mSoQRnmCU0KzQmA3C97a3bbG10blzjVSlrb9fKf8pKWflfcXYpF9WHZAShlG0KLncFvnpvTWjk2obclKVypmqDxIQTiAhlorPirbUDEYI3xf4MgnLDXqpVbZyu5A97uWHfhS7-PriP_MIm3_YtgSU</recordid><startdate>20200601</startdate><enddate>20200601</enddate><creator>Song, Lili</creator><creator>Kim, Do-Sung</creator><creator>Gou, Wenyu</creator><creator>Wang, Jingjing</creator><creator>Wang, Ping</creator><creator>Wei, Zhiguo</creator><creator>Liu, Bei</creator><creator>Li, Zihai</creator><creator>Gou, Kemian</creator><creator>Wang, Hongjun</creator><general>American Physiological Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20200601</creationdate><title>GRP94 regulates M1 macrophage polarization and insulin resistance</title><author>Song, Lili ; Kim, Do-Sung ; Gou, Wenyu ; Wang, Jingjing ; Wang, Ping ; Wei, Zhiguo ; Liu, Bei ; Li, Zihai ; Gou, Kemian ; Wang, Hongjun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c402t-d15da88267e765d5fdf553fc3c8975f81998987dd3069abb3c4b142b2745bfd23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>3T3-L1 Cells</topic><topic>Adipocytes - metabolism</topic><topic>Animals</topic><topic>Coculture Techniques</topic><topic>Cytokines - genetics</topic><topic>Cytokines - immunology</topic><topic>Diet, High-Fat</topic><topic>Glucose Tolerance Test</topic><topic>Inflammation - genetics</topic><topic>Inflammation - immunology</topic><topic>Insulin Resistance - genetics</topic><topic>Insulin Resistance - immunology</topic><topic>Interferon-gamma - pharmacology</topic><topic>Lipopolysaccharides - pharmacology</topic><topic>Macrophage Activation - genetics</topic><topic>Macrophage Activation - immunology</topic><topic>Macrophages - drug effects</topic><topic>Macrophages - immunology</topic><topic>Membrane Glycoproteins - genetics</topic><topic>Membrane Glycoproteins - immunology</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Obesity - genetics</topic><topic>Obesity - immunology</topic><topic>Obesity - metabolism</topic><topic>RNA, Messenger - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Song, Lili</creatorcontrib><creatorcontrib>Kim, Do-Sung</creatorcontrib><creatorcontrib>Gou, Wenyu</creatorcontrib><creatorcontrib>Wang, Jingjing</creatorcontrib><creatorcontrib>Wang, Ping</creatorcontrib><creatorcontrib>Wei, Zhiguo</creatorcontrib><creatorcontrib>Liu, Bei</creatorcontrib><creatorcontrib>Li, Zihai</creatorcontrib><creatorcontrib>Gou, Kemian</creatorcontrib><creatorcontrib>Wang, Hongjun</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American journal of physiology: endocrinology and metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Song, Lili</au><au>Kim, Do-Sung</au><au>Gou, Wenyu</au><au>Wang, Jingjing</au><au>Wang, Ping</au><au>Wei, Zhiguo</au><au>Liu, Bei</au><au>Li, Zihai</au><au>Gou, Kemian</au><au>Wang, Hongjun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>GRP94 regulates M1 macrophage polarization and insulin resistance</atitle><jtitle>American journal of physiology: endocrinology and metabolism</jtitle><addtitle>Am J Physiol Endocrinol Metab</addtitle><date>2020-06-01</date><risdate>2020</risdate><volume>318</volume><issue>6</issue><spage>E1004</spage><epage>E1013</epage><pages>E1004-E1013</pages><issn>0193-1849</issn><eissn>1522-1555</eissn><abstract>Macrophage polarization contributes to obesity-induced insulin resistance. Glucose-regulated protein 94 (GRP94) is an endoplasmic reticulum (ER) chaperone specialized for folding and quality control of secreted and membrane proteins. To determine the role of GRP94 in macrophage polarization and insulin resistance, macrophage-specific GRP94 conditional knockout (KO) mice were challenged with a high-fat diet (HFD). Glucose tolerance, insulin sensitivity, and macrophage composition were compared with control mice. KO mice showed better glucose tolerance and increased insulin sensitivity. Adipose tissues from HFD-KO mice contained lower numbers of M1 macrophages, with lower expression of M1 macrophage markers, than wild-type (WT) mice. In vitro, WT adipocytes cocultured with KO macrophages retained insulin sensitivity, whereas those cultured with WT macrophages did not. In addition, compared with WT bone marrow-derived macrophages (BMDMs), BMDMs from GRP94 KO mice exhibited lower expression of M1 macrophage marker genes following stimulation with LPS or IFN-γ, and exhibited partially increased expression of M2 macrophage marker genes following stimulation with interleukin-4. These findings identify GRP94 as a novel regulator of M1 macrophage polarization and insulin resistance and inflammation.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>32208002</pmid><doi>10.1152/AJPENDO.00542.2019</doi><oa>free_for_read</oa></addata></record> |
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| subjects | 3T3-L1 Cells Adipocytes - metabolism Animals Coculture Techniques Cytokines - genetics Cytokines - immunology Diet, High-Fat Glucose Tolerance Test Inflammation - genetics Inflammation - immunology Insulin Resistance - genetics Insulin Resistance - immunology Interferon-gamma - pharmacology Lipopolysaccharides - pharmacology Macrophage Activation - genetics Macrophage Activation - immunology Macrophages - drug effects Macrophages - immunology Membrane Glycoproteins - genetics Membrane Glycoproteins - immunology Mice Mice, Knockout Obesity - genetics Obesity - immunology Obesity - metabolism RNA, Messenger - metabolism |
| title | GRP94 regulates M1 macrophage polarization and insulin resistance |
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