Ablation of PI3Ky in neurons protects mice from diet-induced obesity MASLD and insulin resistance

Mice with genetic ablation of PI3Ky are protected from diet-induced obesity. However, the cell type responsible for PI3Ky action in obesity remains unknown. We generated mice with conditional deletion of PI3Ky neurons using the nestin promoter to drive the expression of the Cre recombinase (PI3KyNest mice) and investigated their metabolic phenotype in a model of diet-induced obesity. On a chow diet, lean PI3KyNest mice display reduced linear growth and a normal metabolic phenotype. PI3KyNest 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 PI3Ky action in diet-induced obesity depends on its activity in neurons controlling adipose tissue lipolysis. Future clinical studies on PI3Ky inhibitors capable of crossing the brain-blood barrier will reveal the relevance of these findings to humans.