Atf4 protects islet β-cell identity and function under acute glucose-induced stress but promotes β-cell failure in the presence of free fatty acid.

UNLABELLED

Glucolipotoxicity, caused by combined hyperglycemia and hyperlipidemia, results in β-cell failure and type 2 diabetes (T2D) via cellular stress-related mechanisms. Activating transcription factor 4 (Atf4) is an essential effector of stress response. We show here that expression in β-cells is dispensable for glucose homeostasis in young mice, but it is required for β-cell function during aging and under obesity-related metabolic stress. Henceforth, aged deficient β-cells display compromised secretory function under acute hyperglycemia. In contrast, they are resistant to acute free fatty acid-induced loss-of identity and dysfunction. At molecular level, -deficient β-cells down-regulate genes involved in protein translation, reducing β-cell identity gene products under high glucose. They also upregulate several genes involved in lipid metabolism or signaling, likely contributing to their resistance to free fatty acid-induced dysfunction. These results suggest that activation is required for β-cell identity and function under high glucose, but this paradoxically induces β-cell failure in the presence of high levels of free fatty acids. Different branches of Atf4 activity could be manipulated for protecting β-cells from metabolic stress-induced failure.

HIGHLIGHTS

Atf4 is dispensable in β-cells in young miceAtf4 protects β-cells under high glucoseAtf4 exacerbate fatty acid-induced β-cell defectsAtf4 activates translation but depresses lipid-metabolism.