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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-04, Vol.108 (14), p.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: Article
• Language: English
• Subjects: Adipose tissue; Adipose Tissue - cytology; Adipose tissues; animal models; Animals; Biological Sciences; Bone marrow; cell movement; Chemokines; Class Ib Phosphatidylinositol 3-Kinase - antagonists & inhibitors; Class Ib Phosphatidylinositol 3-Kinase - genetics; Diabetes; Flow Cytometry; Gene Expression Profiling; Genetics; Histological Techniques; Infiltration; Inflammation; Inflammation - drug therapy; Inflammation - etiology; Insulin; Insulin Resistance; Leukocytes; Liver; Liver - cytology; Macrophages; Macrophages - physiology; Metabolic disorders; Metabolic syndrome; Mice; Mice, Knockout; noninsulin-dependent diabetes mellitus; Obesity; Obesity - complications; protein subunits; Quinoxalines - pharmacology; Rodents; Thiazolidinediones - pharmacology; Tissues
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1016430108

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.