resistance. HFD feeding markedly increases CD11c-positive macrophages in eWAT as well as in the liver of Pik3cg+/+ SB939 HDAC inhibitor mice, whereas the increase is significantly suppressed by disruption of PI3Kγ. By contrast, the expression of the M2 macrophage marker is not decreased in these tissues of Pik3cg??mice fed a HFD, leading to an increase in the ratio of M2 to M1. This is because M1 macrophages, but not M2 macrophages, abundantly express CCR2 that promotes cell migration into both adipose tissue and liver via PI3Kγ activation. Furthermore, the results of BMT experiments using ob/ob or HFD-fed mice clearly demonstrate that the improved glucose metabolism caused by a lack of PI3Kγ is largely attributed to BM cells.
Together with the results of in vitro experiments, the improved insulin sensitivity and glucose homeostasis associated with decreased inflammatory changes in the adipose tissue ABT-492 inhibitor and liver of obese Pik3cg??mice Fig.4. Loss of PI3Kγ in the ob/ob background improved insulin sensitivity. Time course of body weight and blood glucose in Pik3cg+/+:ob/ob and double-mutant Pik3cg??ob/ob mice. Glucose levels during ITT were determined at the indicated time points after i.p. injection with a bolus of insulin. Glucose and insulin levels during GTT were determined at the indicated time points after i.p. injection with a bolus of glucose. Phosphorylation of Akt in livers and skeletal muscles induced by a bolus injection of insulin was assessed. Expression levels of genes encoded macrophage-related protein , proinflammatory genes , and M2 macrophage-specific genes in eWAT.
Bone marrow-specific PI3Kγ knockout ob/ob mice were generated by bone marrow transplantation. Glucose levels during ITT were determined at the indicated time points after i.p. injection with a bolus of insulin. Glucose and insulin levels during GTT were determined at the indicated time points after i.p. injection with a bolus of glucose. *P 0.05, **P 0.01.5756 | pnas/cgi/doi/10.1073/pnas.1016430108 Kobayashi et al. are largely due to a reduction in the number of infiltrated M1 macrophages that produce proinflammatory adipokines, which thereby promotes systemic insulin resistance, but not the functional changes or differentiation defects in these cells. Hepatic steatosis is also known to exacerbate insulin resistance in obesity and cause liver dysfunction, such as nonalcoholic steatohepatitis.
In the liver of Pik3cg??mice, expression of Pparg and Cidec is significantly decreased without any alterations in genes involved in fatty acid synthesis, whereas genes regulating-oxidation, such as Cpt1a, are up-regulated, consistent with the previous report that Fsp27 suppresses -oxidation and triglyceride turnover in hepatocytes. Fsp27 has been reported to regulate lipid droplet formation downstream of PPARγ in adipocytes, and deletion of Fsp27 leads to protection from dietinduced obesity , although it is unclear whether Fsp27 also functions as a key regulator of lipid droplet formation in hepatocytes. Meanwhile, PPARγ expression levels in the eWAT of Pik3cg??mice are not suppressed differently from those in liver.
It is proposed that, when the capacity of lipid storage in adipose tissue, presumably regulated by PPARγ, reaches a limit, accumulation of lipids in extra-adipose tissue, such as liver and muscle, takes place, leading to insulin resistance. Moreover, it has been suggested that suppression of inflammation reduces the development of hepatic steatosis and insulin resistance. Indeed, treatment with a CCR2 inhibitor ameliorates insulin resistance and hepatic steatosis in db/db mice associated with significant reductions in the expression of