gery, eDepartment of Hematology and Oncology, and hDepartment of Cardiovascular Medicine, Graduate School of Medicine, and BMS-790052 1214735-16-6 bTranslational Systems Biology and Medicine Initiative , University of Tokyo, Tokyo 113-0033, Japan; cDivision of Applied Nutrition, National Institute of Health and Nutrition, Tokyo 162-8636, Japan; fDiscovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., Tochigi 329-0114, Japan; and gDivision of Microbiology, Department of Pathology and Immunology, Akita University School of Medicine, Akita 010-8543, Japan Edited* by Lewis Clayton Cantley, Beth Israel Deaconess Medical Center, Boston, MA, and approved February 23, 2011 Obesity and insulin resistance, the key features of metabolic syndrome, are closely associated with a state of chronic, lowgrade 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 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 A66 PI3K inhibitor 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 , 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 PI3Kγplays 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. Type 2 diabetes and metabolic syndrome, the major risk factors of cardiovascular disease and related death, are explosively increasing worldwide due to a pandemic of obesity that induces a variety of disorders, such as insulin resistance and hepatic steatosis.
Recent studies have revealed that obesity induces hematopoietic cell infiltration into adipose tissue, which in turn enhances adipose tissue inflammation and the secretion of proinflammatory adipokines, leading to systemic insulin resistance. Inhibition of macrophage infiltration into adipose tissue could be considered a therapeutic strategy on the basis of the accumulated evidence of obesity-related metabolic disorders. It has been known that chemokines initiate chemotaxis by binding the corresponding G protein-coupled receptors , leading to activation of class IB phosphoinositide-3 kinase. Upon chemokine stimulation, the unidirectional cytoskeletal rearrangement caused by PI3Kγ promotes cell movement toward the higher concentration of the chemokine.
Furthermore, previous studies using mice lacking p110γ , the catalytic subunit of the PI3Kγ complex, demonstrated that PI3Kγ is essential for chemotaxis in leukocytes, including macrophages. However, the role of PI3Kγ in obesity-induced macrophage infiltration into tissues, systemic inflammation, and the development of insulin resistance is still unknown. To investigate the role of PI3Kγ in obesity-induced insulin resistance, we analyzed Pik3cg�?�?mice fed a high-fat diet and those with a genetically obese diabetic background