Atf4 protects islet b-cell identity and function under acute glucose-induced stress but promotes b-cell failure in the presence of free fatty acid
Glucolipotoxicity, caused by combined hyperglycemia and hyperlipidemia, results in b-cell failure and type 2 diabetes via cellular stress-related mechanisms. Activating transcription factor 4 (Atf4) is an essential effector of stress response. We show here that Atf4 expression in b-cells is minimally required for glucose homeostasis in juvenile and adolescent mice but it is needed for b-cell function during aging and under obesity-related metabolic stress. Henceforth, Atf4-deficient b-cells older than 2 months after birth display compromised secretory function under acute hyperglycemia. In contrast, they are resistant to acute free fatty acid-induced dysfunction and reduced production of several factors essential for b-cell identity. Atf4-deficient b-cells down-regulate genes involved in protein translation. They also upregulate several lipid metabolism or signaling genes, likely contributing to their resistance to free fatty acid-induced dysfunction. These results suggest that Atf4 activation is required for b-cell identity and function under high glucose. But Atf4 activation paradoxically induces b-cell failure in high levels of free fatty acids. Different transcriptional targets of Atf4 could be manipulated to protect b-cells from metabolic stress-induced failure.