Overexpression of Monocyte Chemoattractant Protein-1 in Adipose Tissues Causes Macrophage Recruitment and Insulin Resistance
Adipose tissue expression and circulating concentrations of monocyte chemoattractant protein-1 (MCP-1) correlate positively with adiposity. To ascertain the roles of MCP-1 overexpression in adipose, we generated transgenic mice by utilizing the adipocyte P2 (aP2) promoter (aP2-MCP-1 mice). These mic...
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| creator | Kamei, Nozomu Tobe, Kazuyuki Suzuki, Ryo Ohsugi, Mitsuru Watanabe, Taku Kubota, Naoto Ohtsuka-Kowatari, Norie Kumagai, Katsuyoshi Sakamoto, Kentaro Kobayashi, Masatoshi Yamauchi, Toshimasa Ueki, Kohjiro Oishi, Yumiko Nishimura, Satoshi Manabe, Ichiro Hashimoto, Haruo Ohnishi, Yasuyuki Ogata, Hitomi Tokuyama, Kumpei Tsunoda, Masaki Ide, Tomohiro Murakami, Koji Nagai, Ryozo Kadowaki, Takashi |
| description | Adipose tissue expression and circulating concentrations of monocyte chemoattractant protein-1 (MCP-1) correlate positively with adiposity. To ascertain the roles of MCP-1 overexpression in adipose, we generated transgenic mice by utilizing the adipocyte P2 (aP2) promoter (aP2-MCP-1 mice). These mice had higher plasma MCP-1 concentrations and increased macrophage accumulation in adipose tissues, as confirmed by immunochemical, flow cytometric, and gene expression analyses. Tumor necrosis factor-α and interleukin-6 mRNA levels in white adipose tissue and plasma non-esterified fatty acid levels were increased in transgenic mice. aP2-MCP-1 mice showed insulin resistance, suggesting that inflammatory changes in adipose tissues may be involved in the development of insulin resistance. Insulin resistance in aP2-MCP-1 mice was confirmed by hyperinsulinemic euglycemic clamp studies showing that transgenic mice had lower rates of glucose disappearance and higher endogenous glucose production than wild-type mice. Consistent with this, insulin-induced phosphorylations of Akt were significantly decreased in both skeletal muscles and livers of aP2-MCP-1 mice. MCP-1 pretreatment of isolated skeletal muscle blunted insulin-stimulated glucose uptake, which was partially restored by treatment with the MEK inhibitor U0126, suggesting that circulating MCP-1 may contribute to insulin resistance in aP2-MCP-1 mice. We concluded that both paracrine and endocrine effects of MCP-1 may contribute to the development of insulin resistance in aP2-MCP-1 mice. |
| doi_str_mv | 10.1074/jbc.M601284200 |
| format | Article |
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To ascertain the roles of MCP-1 overexpression in adipose, we generated transgenic mice by utilizing the adipocyte P2 (aP2) promoter (aP2-MCP-1 mice). These mice had higher plasma MCP-1 concentrations and increased macrophage accumulation in adipose tissues, as confirmed by immunochemical, flow cytometric, and gene expression analyses. Tumor necrosis factor-α and interleukin-6 mRNA levels in white adipose tissue and plasma non-esterified fatty acid levels were increased in transgenic mice. aP2-MCP-1 mice showed insulin resistance, suggesting that inflammatory changes in adipose tissues may be involved in the development of insulin resistance. Insulin resistance in aP2-MCP-1 mice was confirmed by hyperinsulinemic euglycemic clamp studies showing that transgenic mice had lower rates of glucose disappearance and higher endogenous glucose production than wild-type mice. Consistent with this, insulin-induced phosphorylations of Akt were significantly decreased in both skeletal muscles and livers of aP2-MCP-1 mice. MCP-1 pretreatment of isolated skeletal muscle blunted insulin-stimulated glucose uptake, which was partially restored by treatment with the MEK inhibitor U0126, suggesting that circulating MCP-1 may contribute to insulin resistance in aP2-MCP-1 mice. We concluded that both paracrine and endocrine effects of MCP-1 may contribute to the development of insulin resistance in aP2-MCP-1 mice.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M601284200</identifier><identifier>PMID: 16809344</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adipose Tissue - cytology ; Adipose Tissue - metabolism ; Animals ; Antimetabolites - metabolism ; Body Weight ; Cells, Cultured ; Chemokine CCL2 - genetics ; Chemokine CCL2 - metabolism ; Deoxyglucose - metabolism ; Diet ; Dietary Fats ; Fatty Acid-Binding Proteins - genetics ; Fatty Acid-Binding Proteins - metabolism ; Fatty Acids, Nonesterified - metabolism ; Glucose - metabolism ; Glucose Clamp Technique ; Insulin - metabolism ; Insulin Resistance - immunology ; Interleukin-6 - genetics ; Interleukin-6 - metabolism ; Macrophages - metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Mice, Transgenic ; Myoblasts, Skeletal - cytology ; Myoblasts, Skeletal - metabolism ; Promoter Regions, Genetic ; Signal Transduction - physiology ; Tumor Necrosis Factor-alpha - genetics ; Tumor Necrosis Factor-alpha - metabolism</subject><ispartof>The Journal of biological chemistry, 2006-09, Vol.281 (36), p.26602-26614</ispartof><rights>2006 © 2006 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c577t-e04afe746b5704859177a4e460556d16691ed03d9319a07eb2c3a6721669e2e83</citedby><cites>FETCH-LOGICAL-c577t-e04afe746b5704859177a4e460556d16691ed03d9319a07eb2c3a6721669e2e83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16809344$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kamei, Nozomu</creatorcontrib><creatorcontrib>Tobe, Kazuyuki</creatorcontrib><creatorcontrib>Suzuki, Ryo</creatorcontrib><creatorcontrib>Ohsugi, Mitsuru</creatorcontrib><creatorcontrib>Watanabe, Taku</creatorcontrib><creatorcontrib>Kubota, Naoto</creatorcontrib><creatorcontrib>Ohtsuka-Kowatari, Norie</creatorcontrib><creatorcontrib>Kumagai, Katsuyoshi</creatorcontrib><creatorcontrib>Sakamoto, Kentaro</creatorcontrib><creatorcontrib>Kobayashi, Masatoshi</creatorcontrib><creatorcontrib>Yamauchi, Toshimasa</creatorcontrib><creatorcontrib>Ueki, Kohjiro</creatorcontrib><creatorcontrib>Oishi, Yumiko</creatorcontrib><creatorcontrib>Nishimura, Satoshi</creatorcontrib><creatorcontrib>Manabe, Ichiro</creatorcontrib><creatorcontrib>Hashimoto, Haruo</creatorcontrib><creatorcontrib>Ohnishi, Yasuyuki</creatorcontrib><creatorcontrib>Ogata, Hitomi</creatorcontrib><creatorcontrib>Tokuyama, Kumpei</creatorcontrib><creatorcontrib>Tsunoda, Masaki</creatorcontrib><creatorcontrib>Ide, Tomohiro</creatorcontrib><creatorcontrib>Murakami, Koji</creatorcontrib><creatorcontrib>Nagai, Ryozo</creatorcontrib><creatorcontrib>Kadowaki, Takashi</creatorcontrib><title>Overexpression of Monocyte Chemoattractant Protein-1 in Adipose Tissues Causes Macrophage Recruitment and Insulin Resistance</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Adipose tissue expression and circulating concentrations of monocyte chemoattractant protein-1 (MCP-1) correlate positively with adiposity. To ascertain the roles of MCP-1 overexpression in adipose, we generated transgenic mice by utilizing the adipocyte P2 (aP2) promoter (aP2-MCP-1 mice). These mice had higher plasma MCP-1 concentrations and increased macrophage accumulation in adipose tissues, as confirmed by immunochemical, flow cytometric, and gene expression analyses. Tumor necrosis factor-α and interleukin-6 mRNA levels in white adipose tissue and plasma non-esterified fatty acid levels were increased in transgenic mice. aP2-MCP-1 mice showed insulin resistance, suggesting that inflammatory changes in adipose tissues may be involved in the development of insulin resistance. Insulin resistance in aP2-MCP-1 mice was confirmed by hyperinsulinemic euglycemic clamp studies showing that transgenic mice had lower rates of glucose disappearance and higher endogenous glucose production than wild-type mice. Consistent with this, insulin-induced phosphorylations of Akt were significantly decreased in both skeletal muscles and livers of aP2-MCP-1 mice. MCP-1 pretreatment of isolated skeletal muscle blunted insulin-stimulated glucose uptake, which was partially restored by treatment with the MEK inhibitor U0126, suggesting that circulating MCP-1 may contribute to insulin resistance in aP2-MCP-1 mice. We concluded that both paracrine and endocrine effects of MCP-1 may contribute to the development of insulin resistance in aP2-MCP-1 mice.</description><subject>Adipose Tissue - cytology</subject><subject>Adipose Tissue - metabolism</subject><subject>Animals</subject><subject>Antimetabolites - metabolism</subject><subject>Body Weight</subject><subject>Cells, Cultured</subject><subject>Chemokine CCL2 - genetics</subject><subject>Chemokine CCL2 - metabolism</subject><subject>Deoxyglucose - metabolism</subject><subject>Diet</subject><subject>Dietary Fats</subject><subject>Fatty Acid-Binding Proteins - genetics</subject><subject>Fatty Acid-Binding Proteins - metabolism</subject><subject>Fatty Acids, Nonesterified - metabolism</subject><subject>Glucose - metabolism</subject><subject>Glucose Clamp Technique</subject><subject>Insulin - metabolism</subject><subject>Insulin Resistance - immunology</subject><subject>Interleukin-6 - genetics</subject><subject>Interleukin-6 - metabolism</subject><subject>Macrophages - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Obese</subject><subject>Mice, Transgenic</subject><subject>Myoblasts, Skeletal - cytology</subject><subject>Myoblasts, Skeletal - metabolism</subject><subject>Promoter Regions, Genetic</subject><subject>Signal Transduction - physiology</subject><subject>Tumor Necrosis Factor-alpha - genetics</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kE1v1DAQhi0EokvhyhF8QNyyjB3HTo7Vio9KXRWVVuJmOc5k19UmDrZTqMSPx6us1BO-zMHP-2rmIeQtgzUDJT7dt3a9lcB4LTjAM7JiUJdFWbGfz8kKgLOi4VV9Rl7FeA_5iYa9JGdM1tCUQqzI3-sHDPhnChij8yP1Pd360dvHhHSzx8GblIKxyYyJfg8-oRsLRt1ILzo3-Yj01sU4Y6QbM8c8tsYGP-3NDukN2jC7NGCOmrGjl2OcDzl5g9HFXGjxNXnRm0PEN6d5Tu6-fL7dfCuurr9ebi6uClsplQoEYXpUQraVAlFXDVPKCBQSqkp2TMqGYQdl15SsMaCw5bY0UvHjD3Ksy3Pycemdgv-Vl016cNHi4WBG9HPUrCl51nYE1wuYj4gxYK-n4AYTHjUDffSts2_95DsH3p2a53bA7gk_Cc7AhwXYu93-twuoW-dtFqt5zXQpNZcSeMbeL1hvvDa74KK--8GBlcCgqRXITNQLgVnUg8Ogo3WYJXa51Cbdefe_Jf8BJr-kYA</recordid><startdate>20060908</startdate><enddate>20060908</enddate><creator>Kamei, Nozomu</creator><creator>Tobe, Kazuyuki</creator><creator>Suzuki, Ryo</creator><creator>Ohsugi, Mitsuru</creator><creator>Watanabe, Taku</creator><creator>Kubota, Naoto</creator><creator>Ohtsuka-Kowatari, Norie</creator><creator>Kumagai, Katsuyoshi</creator><creator>Sakamoto, Kentaro</creator><creator>Kobayashi, Masatoshi</creator><creator>Yamauchi, Toshimasa</creator><creator>Ueki, Kohjiro</creator><creator>Oishi, Yumiko</creator><creator>Nishimura, Satoshi</creator><creator>Manabe, Ichiro</creator><creator>Hashimoto, Haruo</creator><creator>Ohnishi, Yasuyuki</creator><creator>Ogata, Hitomi</creator><creator>Tokuyama, Kumpei</creator><creator>Tsunoda, Masaki</creator><creator>Ide, Tomohiro</creator><creator>Murakami, Koji</creator><creator>Nagai, Ryozo</creator><creator>Kadowaki, Takashi</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</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>7T5</scope><scope>H94</scope></search><sort><creationdate>20060908</creationdate><title>Overexpression of Monocyte Chemoattractant Protein-1 in Adipose Tissues Causes Macrophage Recruitment and Insulin Resistance</title><author>Kamei, Nozomu ; Tobe, Kazuyuki ; Suzuki, Ryo ; Ohsugi, Mitsuru ; Watanabe, Taku ; Kubota, Naoto ; Ohtsuka-Kowatari, Norie ; Kumagai, Katsuyoshi ; Sakamoto, Kentaro ; Kobayashi, Masatoshi ; Yamauchi, Toshimasa ; Ueki, Kohjiro ; Oishi, Yumiko ; Nishimura, Satoshi ; Manabe, Ichiro ; Hashimoto, Haruo ; Ohnishi, Yasuyuki ; Ogata, Hitomi ; Tokuyama, Kumpei ; Tsunoda, Masaki ; Ide, Tomohiro ; Murakami, Koji ; Nagai, Ryozo ; Kadowaki, Takashi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c577t-e04afe746b5704859177a4e460556d16691ed03d9319a07eb2c3a6721669e2e83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Adipose Tissue - 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physiology</topic><topic>Tumor Necrosis Factor-alpha - genetics</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kamei, Nozomu</creatorcontrib><creatorcontrib>Tobe, Kazuyuki</creatorcontrib><creatorcontrib>Suzuki, Ryo</creatorcontrib><creatorcontrib>Ohsugi, Mitsuru</creatorcontrib><creatorcontrib>Watanabe, Taku</creatorcontrib><creatorcontrib>Kubota, Naoto</creatorcontrib><creatorcontrib>Ohtsuka-Kowatari, Norie</creatorcontrib><creatorcontrib>Kumagai, Katsuyoshi</creatorcontrib><creatorcontrib>Sakamoto, Kentaro</creatorcontrib><creatorcontrib>Kobayashi, Masatoshi</creatorcontrib><creatorcontrib>Yamauchi, Toshimasa</creatorcontrib><creatorcontrib>Ueki, Kohjiro</creatorcontrib><creatorcontrib>Oishi, Yumiko</creatorcontrib><creatorcontrib>Nishimura, Satoshi</creatorcontrib><creatorcontrib>Manabe, Ichiro</creatorcontrib><creatorcontrib>Hashimoto, Haruo</creatorcontrib><creatorcontrib>Ohnishi, Yasuyuki</creatorcontrib><creatorcontrib>Ogata, Hitomi</creatorcontrib><creatorcontrib>Tokuyama, Kumpei</creatorcontrib><creatorcontrib>Tsunoda, Masaki</creatorcontrib><creatorcontrib>Ide, Tomohiro</creatorcontrib><creatorcontrib>Murakami, Koji</creatorcontrib><creatorcontrib>Nagai, Ryozo</creatorcontrib><creatorcontrib>Kadowaki, Takashi</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kamei, Nozomu</au><au>Tobe, Kazuyuki</au><au>Suzuki, Ryo</au><au>Ohsugi, Mitsuru</au><au>Watanabe, Taku</au><au>Kubota, Naoto</au><au>Ohtsuka-Kowatari, Norie</au><au>Kumagai, Katsuyoshi</au><au>Sakamoto, Kentaro</au><au>Kobayashi, Masatoshi</au><au>Yamauchi, Toshimasa</au><au>Ueki, Kohjiro</au><au>Oishi, Yumiko</au><au>Nishimura, Satoshi</au><au>Manabe, Ichiro</au><au>Hashimoto, Haruo</au><au>Ohnishi, Yasuyuki</au><au>Ogata, Hitomi</au><au>Tokuyama, Kumpei</au><au>Tsunoda, Masaki</au><au>Ide, Tomohiro</au><au>Murakami, Koji</au><au>Nagai, Ryozo</au><au>Kadowaki, Takashi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Overexpression of Monocyte Chemoattractant Protein-1 in Adipose Tissues Causes Macrophage Recruitment and Insulin Resistance</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2006-09-08</date><risdate>2006</risdate><volume>281</volume><issue>36</issue><spage>26602</spage><epage>26614</epage><pages>26602-26614</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Adipose tissue expression and circulating concentrations of monocyte chemoattractant protein-1 (MCP-1) correlate positively with adiposity. To ascertain the roles of MCP-1 overexpression in adipose, we generated transgenic mice by utilizing the adipocyte P2 (aP2) promoter (aP2-MCP-1 mice). These mice had higher plasma MCP-1 concentrations and increased macrophage accumulation in adipose tissues, as confirmed by immunochemical, flow cytometric, and gene expression analyses. Tumor necrosis factor-α and interleukin-6 mRNA levels in white adipose tissue and plasma non-esterified fatty acid levels were increased in transgenic mice. aP2-MCP-1 mice showed insulin resistance, suggesting that inflammatory changes in adipose tissues may be involved in the development of insulin resistance. Insulin resistance in aP2-MCP-1 mice was confirmed by hyperinsulinemic euglycemic clamp studies showing that transgenic mice had lower rates of glucose disappearance and higher endogenous glucose production than wild-type mice. Consistent with this, insulin-induced phosphorylations of Akt were significantly decreased in both skeletal muscles and livers of aP2-MCP-1 mice. MCP-1 pretreatment of isolated skeletal muscle blunted insulin-stimulated glucose uptake, which was partially restored by treatment with the MEK inhibitor U0126, suggesting that circulating MCP-1 may contribute to insulin resistance in aP2-MCP-1 mice. We concluded that both paracrine and endocrine effects of MCP-1 may contribute to the development of insulin resistance in aP2-MCP-1 mice.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>16809344</pmid><doi>10.1074/jbc.M601284200</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of biological chemistry, 2006-09, Vol.281 (36), p.26602-26614 |
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| subjects | Adipose Tissue - cytology Adipose Tissue - metabolism Animals Antimetabolites - metabolism Body Weight Cells, Cultured Chemokine CCL2 - genetics Chemokine CCL2 - metabolism Deoxyglucose - metabolism Diet Dietary Fats Fatty Acid-Binding Proteins - genetics Fatty Acid-Binding Proteins - metabolism Fatty Acids, Nonesterified - metabolism Glucose - metabolism Glucose Clamp Technique Insulin - metabolism Insulin Resistance - immunology Interleukin-6 - genetics Interleukin-6 - metabolism Macrophages - metabolism Mice Mice, Inbred C57BL Mice, Obese Mice, Transgenic Myoblasts, Skeletal - cytology Myoblasts, Skeletal - metabolism Promoter Regions, Genetic Signal Transduction - physiology Tumor Necrosis Factor-alpha - genetics Tumor Necrosis Factor-alpha - metabolism |
| title | Overexpression of Monocyte Chemoattractant Protein-1 in Adipose Tissues Causes Macrophage Recruitment and Insulin Resistance |
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