Loss of Pdk1-Foxo1 signaling in myeloid cells predisposes to adipose tissue inflammation and insulin resistance

Yoshinaga Kawano, Jun Nakae, Nobuyuki Watanabe, Shiho Fujisaka, Kristy Iskandar, Risa Sekioka, Yoshitake Hayashi, Kazuyuki Tobe, Masato Kasuga, Tetsuo Noda, Akihiko Yoshimura, Masafumi Onodera, Hiroshi Itoh

研究成果: Article査読

45 被引用数 (Scopus)

抄録

Chronic inflammation in adipose tissue contributes to obesity-related insulin resistance. The 3-phosphoinositide-dependent protein kinase 1 (Pdk1)/forkhead transcription factor (Foxo1) pathway is important in regulating glucose and energy homeostasis, but little is known about this pathway in adipose tissue macrophages (ATMs). To investigate this, we generated transgenic mice that carried macrophage/granulocyte-specific mutations, including a Pdk1 knockout (LysMPdk1 -/-), a Pdk1 knockout with transactivation- defective Foxo1 (Δ256LysMPdk1 -/-), a constitutively active nuclear (CN) Foxo1 (CNFoxo1 LysM), or a transactivation-defective Foxo1 (Δ256Foxo1 LysM). We analyzed glucose metabolism and gene expression in ATM populations isolated with fluorescence-activated cell sorting. The LysMPdk1 -/- mice exhibited elevated M1 macrophages in adipose tissue and insulin resistance. Overexpression of transactivation-defective Foxo1 rescued these phenotypes. CNFoxo1 LysM promoted transcription of the C-C motif chemokine receptor 2 (Ccr2) in ATMs and increased M1 macrophages in adipose tissue. On a high-fat diet, CNFoxo1 LysMmice exhibited insulin resistance. Pdk1 deletion or Foxo1 activation in bone marrow-derived macrophages abolished insulin and interleukin-4 induction of genes involved in alternative macrophage activation. Thus, Pdk1 regulated macrophage infiltration by inhibiting Foxo1-induced Ccr2 expression. This shows that the macrophage Pdk1/Foxo1 pathway is important in regulating insulin sensitivity in vivo.

本文言語English
ページ(範囲)1935-1948
ページ数14
ジャーナルDiabetes
61
8
DOI
出版ステータスPublished - 2012 8月

ASJC Scopus subject areas

  • 内科学
  • 内分泌学、糖尿病および代謝内科学

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