Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance

Nozomu Kamei, Kazuyuki Tobe, Ryo Suzuki, Mitsuru Ohsugi, Taku Watanabe, Naoto Kubota, Norie Ohtsuka-Kowatari, Katsuyoshi Kumagai, Kentaro Sakamoto, Masatoshi Kobayashi, Toshimasa Yamauchi, Kohjiro Ueki, Yumiko Oishi, Satoshi Nishimura, Ichiro Manabe, Haruo Hashimoto, Yasuyuki Ohnishi, Hitomi Ogata, Kumpei Tokuyama, Masaki TsunodaTomohiro Ide, Koji Murakami, Ryozo Nagai, Takashi Kadowaki*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

757 Scopus citations

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 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.

Original languageEnglish
Pages (from-to)26602-26614
Number of pages13
JournalJournal of Biological Chemistry
Volume281
Issue number36
DOIs
StatePublished - 2006/09/08

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance'. Together they form a unique fingerprint.

Cite this