title: Blockade of class IB phosphoinositide-3 kinase ameliorates obesity-induced inflammation and insulin resistance.
abstract: Obesity and insulin resistance, the key features of metabolic syndrome, are closely associated with a state of chronic, low-grade inflammation characterized by abnormal macrophage infiltration into adipose tissues. Although it has been reported that chemokines promote leukocyte migration by activating class IB phosphoinositide-3 kinase (PI3Kγ) in inflammatory states, little is known about the role of PI3Kγ in obesity-induced macrophage infiltration into tissues, systemic inflammation, and the development of insulin resistance. In the present study, we used murine models of both diet-induced and genetically induced obesity to examine the role of PI3Kγ in the accumulation of tissue macrophages and the development of obesity-induced insulin resistance. Mice lacking p110γ (Pik3cg(-/-)), the catalytic subunit of PI3Kγ, exhibited improved systemic insulin sensitivity with enhanced insulin signaling in the tissues of obese animals. In adipose tissues and livers of obese Pik3cg(-/-) mice, the numbers of infiltrated proinflammatory macrophages were markedly reduced, leading to suppression of inflammatory reactions in these tissues. Furthermore, bone marrow-specific deletion and pharmacological blockade of PI3Kγ also ameliorated obesity-induced macrophage infiltration and insulin resistance. These data suggest that PI3Kγ plays a crucial role in the development of both obesity-induced inflammation and systemic insulin resistance and that PI3Kγ can be a therapeutic target for type 2 diabetes.
authors: Department of Metabolic Diseases, Graduate School of Medicine, and Translational Systems Biology and Medicine Initiative, University of Tokyo, Tokyo 113-0033, Japan.
authors: Naoki
authors: N
authors: Kobayashi
authors: Kohjiro
authors: K
authors: Ueki
authors: Yukiko
authors: Y
authors: Okazaki
authors: Aya
authors: A
authors: Iwane
authors: Naoto
authors: N
authors: Kubota
authors: Mitsuru
authors: M
authors: Ohsugi
authors: Motoharu
authors: M
authors: Awazawa
authors: Masatoshi
authors: M
authors: Kobayashi
authors: Takayoshi
authors: T
authors: Sasako
authors: Kazuma
authors: K
authors: Kaneko
authors: Miho
authors: M
authors: Suzuki
authors: Yoshitaka
authors: Y
authors: Nishikawa
authors: Kazuo
authors: K
authors: Hara
authors: Kotaro
authors: K
authors: Yoshimura
authors: Isao
authors: I
authors: Koshima
authors: Susumu
authors: S
authors: Goyama
authors: Koji
authors: K
authors: Murakami
authors: Junko
authors: J
authors: Sasaki
authors: Ryozo
authors: R
authors: Nagai
authors: Mineo
authors: M
authors: Kurokawa
authors: Takehiko
authors: T
authors: Sasaki
authors: Takashi
authors: T
authors: Kadowaki
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006652:Histological Techniques; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology; D007333:Insulin Resistance; D008099:Liver / Q000166:cytology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D045162:Thiazolidinediones; D058544:Class Ib Phosphatidylinositol 3-Kinase