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

Phosphoinositide 3-kinase gamma (PI3Kgamma) plays a central role in inflammation, allergy, cardiovascular, and metabolic disease. Obesity is accompanied by chronic, low-grade inflammation. As PI3Kgamma plays a major role in leukocyte recruitment, targeting of PI3Kgamma has been considered to be a strategy for attenuating progression of obesity to insulin resistance and type 2 diabetes. Indeed, PI3Kgamma null mice are protected from high fat diet-induced obesity, metabolic inflammation, fatty liver, and insulin resistance. The lean phenotype of the PI3Kgamma-null mice has been linked to increased thermogenesis and energy expenditure. Surprisingly, the increase in fat mass and metabolic aberrations were not linked to PI3Kgamma activity in the hematopoietic compartment. Thermogenesis and oxygen consumption are modulated by PI3Kgamma lipid kinase-dependent and -independent signaling mechanisms. PI3Kgamma signaling controls metabolic and inflammatory stress, and may provide an entry point for therapeutic strategies in metabolic disease, inflammation, and cardiovascular disease.