Blockade of class IB phosphoinositide-3 kinase ameliorates obesity-induced inflammation and insulin resistance

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 activati...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 108; no. 14; pp. 5753 - 5758
Main Authors Kobayashi, Naoki, Ueki, Kohjiro, Okazaki, Yukiko, Iwane, Aya, Kubota, Naoto, Ohsugi, Mitsuru, Awazawa, Motoharu, Kobayashi, Masatoshi, Sasako, Takayoshi, Kaneko, Kazuma, Suzuki, Miho, Nishikawa, Yoshitaka, Hara, Kazuo, Yoshimura, Kotaro, Koshima, Isao, Goyama, Susumu, Murakami, Koji, Sasaki, Junko, Nagai, Ryozo, Kurokawa, Mineo, Sasaki, Takehiko, Kadowaki, Takashi
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 05.04.2011
National Acad Sciences
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Summary: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.
Bibliography:http://dx.doi.org/10.1073/pnas.1016430108
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Edited* by Lewis Clayton Cantley, Beth Israel Deaconess Medical Center, Boston, MA, and approved February 23, 2011 (received for review November 2, 2010)
Author contributions: N. Kobayashi, K.U., and T.K. designed research; N. Kobayashi, K.U., Y.O., A.I., N. Kubota, M.O., M.A., M. Kobayashi, T. Sasako, K.K., M.S., Y.N., and S.G. performed research; K.Y., I.K., K.M., J.S., and T. Sasaki contributed new reagents/analytic tools; N. Kobayashi, K.U., K.H., R.N., and M. Kurokawa analyzed data; and N. Kobayashi, K.U., and T.K. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1016430108