Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1–dependent manner

Transcription factor FoxO1 promotes hepatic glucose production. Genetic inhibition of FoxO1 function prevents diabetes in experimental animal models, providing impetus to identify pharmacological approaches to modulate its function. Altered Notch signaling is seen in tumorigenesis, and Notch antagonists are in clinical testing for cancer application. Here, we report that FoxO1 and Notch coordinately regulate hepatic glucose metabolism. Combined haploinsufficiency of FoxO1 and Notch1 markedly improves insulin sensitivity in diet-induced insulin resistance, as does liver-specific knockout of the Notch transcriptional effector, Rbp-Jk. Conversely, Notch1 gain-of-function promotes insulin resistance in a FoxO1-dependent manner and induces Glucose-6-phosphatase expression. Pharmacological blockade of Notch signaling with γ-secretase inhibitors improves insulin sensitivity following in vivo administration in lean and in obese, insulin-resistant mice. The data identify a heretofore unknown metabolic function of Notch, and suggest that Notch inhibition is beneficial to diabetes treatment, in part by helping to offset excessive FoxO1–driven hepatic glucose production.