-regulated. These data suggest that loss of PI3Kγ ameliorated obesity-induced insulin resistance through the reduction of macrophage infiltration and inflammation even in a genetically obese model and that a large part of these beneficial effects of PI3Kγ deficiency on glucose metabolism NVP-BEP800 847559-80-2 appears to be independent of leptin signaling and body weight change. Bone Marrow-Specific Deletion of PI3Kγ Ameliorates Obesity-Induced Diabetes. Although PI3Kγ is almost exclusively expressed in hematopoietic cells, to rule out the possibility that PI3Kγ in extrahematopoietic parenchymal tissues might play some role in glucose metabolism, we generated a bone marrow -specific PI3Kγ deletion in ob/ob mice by BM transplantation.
Compared with the control mice that received the Pik3cg+/+ BM cells, Pik3cg?�BMT A-966492 PARP inhibitor ob/ob mice displayed improved glucose levels, systemic insulin sensitivity, and glucose intolerance , as observed in ob/ob mice systemically lacking Pik3cg?? These data strongly suggest that the metabolic phenotypes of Pik3cg??ob/ ob mice are mainly owing to the lack of PI3Kγ in BM-derived cells. Moreover, we also confirmed that BM-specific Pik3cg?? mice fed a HFD exhibited the phenotypes similar to those of mice systemically lacking Pik3cg?? Furthermore, the in vitro studies revealed that lack of PI3Kγ did not significantly alter expression of Itgax in BM-derived macrophages , induction of Mgl2 in IL-4–stimulated alternative activation in BMDM, or LPS-stimulated proinflammatory cytokine expression in peritoneal macrophages. Blockade of PI3Kγ by a Pharmacological Inhibitor Ameliorated Obesity-Induced Diabetes.
Finally, we addressed whether pharmacological inhibition of PI3Kγ could ameliorate insulin resistance in obese diabetic animal models using AS-605240, a small-molecule inhibitor for PI3Kγ. We confirmed that AS-605240 selectively blocked class IB PI3K signaling in cultured macrophages , as shown in the previous reports. Treatment with 10 mg/kg/d of AS-605240 lowered blood glucose levels, with an associated significant improvement of both insulin sensitivity and glucose tolerance without affecting body weight. A total of 30 mg/kg/d of AS-605240 displayed more profound effects with slightly less weight gain. Moreover, AS-605240 dose-dependently reduced the abundance of ATMs as estimated by F4/80 staining and the expression levels of macrophage markers in eWAT.
As a consequence, the circulating levels of MCP-1 were also reduced in ob/ob mice treated with AS-605240. We also confirmed that Pik3cg+/+ mice fed a HFD treated with AS-605240 exhibited metabolic phenotypes very similar to those of Pik3cg??mice. These findings strongly suggest that pharmacological intervention by inhibiting PI3Kγ is effective even after establishment of a morbidly obese condition. Discussion Obesity causes a variety of metabolic disorders, including diabetes and fatty liver disease, initiated by macrophage infiltration into adipose tissue and presumably also into liver. Previous studies have shown that MCP-1 triggers this macrophage infiltration and that modulation of the MCP-1/CCR2 signaling by genetic disruption or treatment with an inhibitory molecule can ameliorate obesity-induced insulin resistance.
Other chemokines have recently been suggested to also promote macrophage infiltration in obesity. Receptors for these chemokines, including CCR2, are GPCRs, of which PI3Kγ lies downstream and mediates the signal to promote cell movement in response to chemokine stimulation. Here, we show that suppression of PI3Kγ activity attenuates obesity-induced proinflammatory macrophage infiltration into adipose tissue and liver, leading to improvement of insulin