Hepatic FoxO1 loss leads to pancreatic β cell deficiency via liver-derived C18/22/24 ceramides.

Preserving pancreatic β cells is requisite for antihyperglycemic strategy. Hepatic FoxO1 represents a promising therapeutic target. However, the systemic consequences on β cell homeostasis upon hepatic FoxO1 loss and the underlying mechanism remain largely unexplored. Using liver-specific Foxo1 knockdown mouse and transgenic zebrafish models, we uncover that hepatic FoxO1 loss leads to β cell deficiency via triggering apoptosis. Lipidomic and pharmacological analyses identify that hepatic FoxO1 loss increases the liver-derived C18/22/24 ceramides, which contribute to apoptosis by inhibiting the AKT-mTORC1 pathway in β cells. The elevated C18/22/24 ceramide production is due to the upregulated transcription of hepatic ceramide synthase 2/4, while ChIP-seq and luciferase assays further decipher that FoxO1 acts as a transcriptional repressor of Cers2/4. We, therefore, report an inter-organ signal from liver-derived ceramides to pancreatic β cell homeostasis upon hepatic FoxO1 loss. These findings provide insights for therapeutic strategies aimed at preserving β cells and ameliorating hyperglycemia.