Inhibition of phosphoinositide 3-kinase γ attenuates inflammation, obesity, and cardiovascular risk factors.

Phosphoinositide 3-kinase γ (PI3Kγ) plays a central role in inflammation, allergy, cardiovascular, and metabolic disease. Obesity is accompanied by chronic, low-grade inflammation. As PI3Kγ plays a major role in leukocyte recruitment, targeting of PI3Kγ has been considered to be a strategy for attenuating progression of obesity to insulin resistance and type 2 diabetes. Indeed, PI3Kγ null mice are protected from high fat diet-induced obesity, metabolic inflammation, fatty liver, and insulin resistance. The lean phenotype of the PI3Kγ-null mice has been linked to increased thermogenesis and energy expenditure. Surprisingly, the increase in fat mass and metabolic aberrations were not linked to PI3Kγ activity in the hematopoietic compartment. Thermogenesis and oxygen consumption are modulated by PI3Kγ lipid kinase-dependent and -independent signaling mechanisms. PI3Kγ signaling controls metabolic and inflammatory stress, and may provide an entry point for therapeutic strategies in metabolic disease, inflammation, and cardiovascular disease.