Loss of Pdk1-Foxo1 Signaling in Myeloid Cells Predisposes to Adipose Tissue Inflammation and Insulin Resistance

  1. Hiroshi Itoh1
  1. 1Frontier Medicine on Metabolic Syndrome, Division of Endocrinology, Metabolism, and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
  2. 2Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan
  3. 3Department of Internal Medicine, University of Toyama, Toyama, Japan
  4. 4Pediatric Research Office, Department of Child Health, Faculty of Medicine, Universitas Gadjah Mada, Sardjito Hospital, Yogyakarta, Indonesia
  5. 5Division of Molecular Medicine and Medical Genetics, International Center for Medical Research and Treatment, Kobe University Graduate School of Medicine, Kobe, Japan
  6. 6Research Institute, International Medical Center of Japan, Tokyo, Japan
  7. 7Department of Cell Biology, Japanese Foundation for Cancer Research, Cancer Institute, Tokyo, Japan
  8. 8Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
  1. Corresponding author: Jun Nakae, jnakae35{at}sc.itc.keio.ac.jp.

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 (CNFoxo1LysM), or a transactivation-defective Foxo1 (Δ256Foxo1LysM). 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. CNFoxo1LysM 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, CNFoxo1LysM mice 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.

Footnotes

  • Received June 6, 2011.
  • Accepted March 6, 2012.

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  1. Diabetes vol. 61 no. 8 1935-1948
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