ere increased, whereas these increases were significantly LY2228820 862507-23-1 attenuated by PI3Kγ deletion. Furthermore, circulating monocyte chemotactic protein-1 levels also decreased with a trend toward reductions in c-jun N-terminal kinase, and IκB kinase phosphorylation in the eWAT of Pik3cg??mice. Taken together, these data suggest that the loss of PI3Kγ specifically suppresses M1 macrophage infiltration, leading to suppression of HFD-induced inflammation in adipose tissue, and finally leading to improved insulin sensitivity. However, it remained possible that deficiency of PI3Kγ would modulate insulin sensitivity through other mechanisms. Indeed, we found that elevated leptin levels observed during HFD feeding were significantly decreased with a trend to decrease Socs3 expression by deletion of PI3Kγ , suggesting improved leptin sensitivity.
This could be caused by reductions of proinflammatory adipokines and also A 922500 Diacylglycerol acyltransferase 1 inhibitor through reduced macrophage infiltration in the hypothalamus by deletion of PI3Kγ, as evidenced by deceased expression of Emr1. However, the effect appeared very limited because food intake, energy expenditure, and genes regulated by leptin were not altered by deletion of PI3Kγ.Loss of PI3Kγ Ameliorated Diet-Induced Hepatic Steatosis. Next, we assessed the impact of PI3Kγ deficiency on HFD-induced hepatic steatosis, which is known to be tightly associated with hepatic and systemic insulin resistance. Interestingly, hepatic triglyceride content was significantly suppressed in the livers of Pik3cg??mice compared with that seen in Pik3cg+/+ mice, which is consistent with the histological findings by hematoxylin and eosin staining.
Hepatic steatosis can be caused by overproduction of fatty acid, reduced fatty acid oxidation, increased lipid transport, and their combinations. Expression levels of genes involved in fatty acid synthesis tested here were not affected by PI3Kγ deletion , whereas Cpt1a, which involves fatty acid oxidation, was significantly increased in HFDfed Pik3cg??mice compared with Pik3cg+/+ mice. Intriguingly, expression of Cidec and Cd36 in HFD-fed conditions was markedly suppressed in the livers of Pik3cg??mice. Expression of peroxisome proliferator-activated receptors , which is known to directly regulate Cidec, Cd36, Scd1, and Pparg itself , was also significantly decreased by deletion of PI3Kγ.
Moreover, similar to findings seen witheWAT,expression of Cd68, Tnf, Ccl2, and its receptor Ccr2 was significantly decreased in the livers of Pik3cg??mice compared with that seen in Pik3cg+/+ mice , and M2 macrophage markers were up-regulated. The MCP-1/chemokine receptor 2 pathway, which lies upstream of PI3Kγ, has been reported to contribute to the development of hepatic steatosis , and our findings may provide a missing link between hepatic steatosis and inflammation. Loss of PI3Kγ in ob/ob Mice Reduced Inflammatory Changes in Adipose Tissue, Leading to Improvement of Insulin Sensitivity. To further assess the role of PI3Kγ in obesity-induced inflammation and insulin resistance, we generated Pik3cg??mice with a leptindeficient background. Although Pik3cg??ob/ ob mice gained body weight in a similar manner compared with Pik3cg+/+:ob/ob mice, they displayed lower blood glucose levels up to 20 wk of age.
Similarly, Pik3cg??ob/ob mice also displayed significantly decreased glucose levels in a fasted state as well as during ITT and GTT along with enhanced insulin-stimulated Akt phosphorylation in both liver and muscle of Pik3cg??ob/ob mice. In addition, the expression of Emr1, Cd68, and Tnf in the eWAT of Pik3cg??ob/ob mice was also significantly decreased , whereas M2 macrophage markers were up