CD36 in liver. Although it remains unclear how PI3Kγ deficiency causes the suppression of lipid accumulation in liver, it is possible that inhibition Geldanamycin 30562-34-6 of macrophage infiltration into adipose tissue and liver, and the subsequent reduction of inflammatory changes, can decrease PPARγ expression in liver but not in adipocytes. This may inhibit the ectopic lipid accumulation, leading to systemic insulin sensitivity, although it should be explored how PPARγ is regulated in these tissues. Inhibitors for PI3Kδ and PI3Kγ are expected to be therapeutic agents for chronic inflammatory diseases. Indeed, pharmacological inhibition of PI3Kγ ameliorates rheumatoid arthritis, lupus nephritis, and atherosclerosis in mouse models , and here we provide evidence that the PI3Kγinhibition is also promising for treatment of obesity-induced diabetes.
Because multiple chemokine-signaling pathways can be involved in macrophage infiltration and inflammation in an obese context, and because inhibition of PI3Kγ could suppress macrophage migration caused by all these chemokines , blockade of PI3Kγ appears to have advantages compared with the strategies to inhibit single chemokine signaling, such as MCP-1 ABT-737 852808-04-9 or CCR2, which have been shown to improve insulin sensitivity in obese mice. However, a highly selective inhibitor for PI3Kγ, which does not affect class IA PI3Ks and other kinases, should be developed and carefully evaluated for clinical use to avoid potential adverse effects, such as inhibition of insulin signaling. Nevertheless, our data suggest that PI3Kγinhibition can be a strategy for treating obesity-induced insulin resistance.
We have clearly demonstrated that PI3Kγ plays a crucial role in obesity-induced inflammation, hepatic steatosis, and systemic insulin resistance and that inhibition of PI3Kγ activity ameliorates obesity-induced insulin resistance, at least in part, due to the reductions in macrophage infiltration and subsequent inflammatory responses in both adipose tissue and liver. These findings provide a possibility for a therapeutic approach to obesity-induced diabetes and fatty liver disease. Materials and Methods Mice. We generated Pik3cg??mice as previously described and used these mice after they were backcrossed to C57BL/6J mice for more than 16 generations with C57BL/6J mice as the controls. Pik3cg??ob/ob mice were generated by intercrossing Pik3cg+/?ob/+ mice.
All mice were housed under a 12-h light/12-h dark cycle and had free access to sterile water and pellet food ad libitum except when fed a limited HFD. The animal care and experimental procedures were approved by the Animal Care Committee of the University of Tokyo. Metabolic Studies. Male Pik3cg??and Pik3cg+/+ mice were fed a standard chow or high-fat/high-caloric diet. For ITTs, mice received i.p. injections of human insulin in the ad libitum feeding state. For GTTs, mice received i.p. injections of glucose after an overnight fast. Blood glucose levels were measured using a Glutest sensor at the indicated time points, and the plasma insulin levels were measured using a RIA kit , as previously described. Insulin-Signaling Analysis.
Mice were anesthetized after 16 h of fasting, and human insulin was injected into the inferior vena cava. After 5 min, tissues were quickly excised and frozen in liquid nitrogen. Tissue lysates were prepared and used for immunoprecipitation and immunoblotting as previously described. Fig.5. Blockade of PI3Kγ by a pharmacological inhibitor ameliorated diabetes in ob/ob mice. ob/ob mice were treated with a PI3Kγ inhibitor, AS-605240, from 6 wk of age for 8 wk. Age-matched C57BL/6J mice served as lean controls. Time course of blood glucose