Ablation of PI3Kγ in neurons protects mice from diet-induced obesity MASLD and insulin resistance.

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Mice with genetic ablation of PI3Kγ are protected from diet-induced obesity. However, the cell type responsible for PI3Kγ action in obesity remains unknown. We generated mice with conditional deletion of PI3Kγ in neurons using the nestin promoter to drive the expression of the Cre recombinase (PI3KγNest mice) and investigated their metabolic phenotype in a model of diet-induced obesity. On a chow diet, lean PI3KγNest mice display reduced linear growth and a normal metabolic phenotype. PI3KγNest mice were largely protected from diet-induced obesity and liver steatosis and showed improved glucose tolerance and insulin sensitivity. This phenotype was associated with increased phosphorylation of hormone-sensitive lipase (HSL) at protein kinase A (PKA) sites in white fat. It is concluded that PI3Kγ action in diet-induced obesity depends on its activity in neurons controlling adipose tissue lipolysis. Future clinical studies on PI3Kγ inhibitors capable of crossing the brain-blood barrier will reveal the relevance of these findings to humans.