TY - JOUR
T1 - Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance
AU - Kamei, Nozomu
AU - Tobe, Kazuyuki
AU - Suzuki, Ryo
AU - Ohsugi, Mitsuru
AU - Watanabe, Taku
AU - Kubota, Naoto
AU - Ohtsuka-Kowatari, Norie
AU - Kumagai, Katsuyoshi
AU - Sakamoto, Kentaro
AU - Kobayashi, Masatoshi
AU - Yamauchi, Toshimasa
AU - Ueki, Kohjiro
AU - Oishi, Yumiko
AU - Nishimura, Satoshi
AU - Manabe, Ichiro
AU - Hashimoto, Haruo
AU - Ohnishi, Yasuyuki
AU - Ogata, Hitomi
AU - Tokuyama, Kumpei
AU - Tsunoda, Masaki
AU - Ide, Tomohiro
AU - Murakami, Koji
AU - Nagai, Ryozo
AU - Kadowaki, Takashi
PY - 2006/9/8
Y1 - 2006/9/8
N2 - 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 maybe 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.
AB - 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 maybe 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.
UR - http://www.scopus.com/inward/record.url?scp=33748750917&partnerID=8YFLogxK
U2 - 10.1074/jbc.M601284200
DO - 10.1074/jbc.M601284200
M3 - 学術論文
C2 - 16809344
AN - SCOPUS:33748750917
SN - 0021-9258
VL - 281
SP - 26602
EP - 26614
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 36
ER -