title: Loss of Pdk1-Foxo1 signaling in myeloid cells predisposes to adipose tissue inflammation and insulin resistance.
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(LysM) 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.
authors.affiliation: Frontier Medicine on Metabolic Syndrome, Division of Endocrinology, Metabolism, and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Yoshinaga
authors.initials: Y
authors.lastname: Kawano
authors.forename: Jun
authors.initials: J
authors.lastname: Nakae
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Watanabe
authors.forename: Shiho
authors.initials: S
authors.lastname: Fujisaka
authors.forename: Kristy
authors.initials: K
authors.lastname: Iskandar
authors.forename: Risa
authors.initials: R
authors.lastname: Sekioka
authors.forename: Yoshitake
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tobe
authors.forename: Masato
authors.initials: M
authors.lastname: Kasuga
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Masafumi
authors.initials: M
authors.lastname: Onodera
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000273:Adipose Tissue / Q000473:pathology / Q000502:physiology; D000818:Animals; D059305:Diet, High-Fat; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D007333:Insulin Resistance / Q000502:physiology*; D015847:Interleukin-4 / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015434:Panniculitis / Q000209:etiology* / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D054390:Receptors, CCR2 / Q000096:biosynthesis
chemical_list: C515335:Ccr2 protein, mouse; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D054390:Receptors, CCR2; D015847:Interleukin-4; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases