title: Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance.
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-alpha 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.
authors.affiliation: Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Kamei
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tobe
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ohsugi
authors.forename: Taku
authors.initials: T
authors.lastname: Watanabe
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.forename: Norie
authors.initials: N
authors.lastname: Ohtsuka-Kowatari
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Kumagai
authors.forename: Kentaro
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Kohjiro
authors.initials: K
authors.lastname: Ueki
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Oishi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nishimura
authors.forename: Ichiro
authors.initials: I
authors.lastname: Manabe
authors.forename: Haruo
authors.initials: H
authors.lastname: Hashimoto
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ohnishi
authors.forename: Hitomi
authors.initials: H
authors.lastname: Ogata
authors.forename: Kumpei
authors.initials: K
authors.lastname: Tokuyama
authors.forename: Masaki
authors.initials: M
authors.lastname: Tsunoda
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ide
authors.forename: Koji
authors.initials: K
authors.lastname: Murakami
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D000963:Antimetabolites / Q000378:metabolism; D001835:Body Weight; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D003847:Deoxyglucose / Q000378:metabolism; D004032:Diet; D004041:Dietary Fats; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000276:immunology*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000963:Antimetabolites; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004041:Dietary Fats; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D003847:Deoxyglucose; D005947:Glucose