Endocrine Abstracts

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). The LysMPdk1-/- mice exhibited elevated M1 macrophages in adipose tissue and insulin resistance. Insulin-stimulated IRS1 or IRS2 and Akt phosphorylation were significantly decreased in epididymal fat and liver of LysMPdk1-/- compared to control mice. F4/80+ Kupffer cells in liver were significantly decreased. Furthermore, expression levels of Il4 and Il10 were significantly decreased and bone marrow derived Cd11b+ cells were significantly increased in liver of LysMPdk1-/-. LysMPdk1-/- exhibit increased Ccr2 expression in stromal vascular fraction (SVF) and peritoneal macrophage. Transwell migration assays revealed that Pdk1-deficient bone marrow derived macrophages (BMDM) exhibited significantly increased capacity of migration compared to BMDM from control. 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. Furthermore, Pdk1 deletion or Foxo1 activation in bone marrow-derived macrophages abolished insulin- and interleukin-4-induction of genes involved in alternative macrophage activation. These data suggested that Pdk1-Foxo1 pathway regulates migration and polarization of macrophage and plays an important role in the regulation of insulin sensitivity in vivo.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.