Open AccessBlockade of class IB phosphoinositide-3 kinase ameliorates obesity-induced inflammation and insulin resistance
Author(s) -
Naoki Kobayashi,
Kohjiro Ueki,
Yukiko Okazaki,
Aya Iwane,
Naoto Kubota,
Mitsuru Ohsugi,
Motoharu Awazawa,
Masatoshi Kobayashi,
Takayoshi Sasako,
Kazuma Kaneko,
Miho Suzuki,
Yoshitaka Nishikawa,
Kazuo Hara,
Kotaro Yoshimura,
Isao Koshima,
Susumu Goyama,
Koji Murakami,
Junko Sasaki,
Ryozo Nagai,
Mineo Kurokawa,
Takehiko Sasaki,
Takashi Kadowaki
Publication year - 2011
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1016430108
Subject(s) - insulin resistance , adipose tissue , inflammation , proinflammatory cytokine , endocrinology , medicine , insulin , insulin receptor , pi3k/akt/mtor pathway , systemic inflammation , chemokine , phosphoinositide 3 kinase , biology , immunology , signal transduction , microbiology and biotechnology
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 obesePik3cg−/− 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.