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

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36 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1935-1948
Number of pages14
JournalDiabetes
Volume61
Issue number8
DOIs
Publication statusPublished - 2012 Aug 1

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Kawano, Y., Nakae, J., Watanabe, N., Fujisaka, S., Iskandar, K., Sekioka, R., Hayashi, Y., Tobe, K., Kasuga, M., Noda, T., Yoshimura, A., Onodera, M., & Itoh, H. (2012). Loss of Pdk1-Foxo1 signaling in myeloid cells predisposes to adipose tissue inflammation and insulin resistance. Diabetes, 61(8), 1935-1948. https://doi.org/10.2337/db11-0770