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

It is generally agreed that glucolipotoxicity, caused by combined hyperglycemia and hyperlipidemia, results in beta-cell failure and type 2 diabetes (T2D) via stress response-related mechanisms. Activating transcription factor 4 (Atf4) is an essential effector of stress response. Using beta-cell specific gene knockout in mice, we show here that Atf4 is dispensable in young mice for glucose homeostasis. But it is required for beta-cell function during aging and under long-term obesity-related metabolic stress. Henceforth, aged Atf4-deficient beta-cells display compromised function under acute hyperglycemia. In contrast, these mutant beta-cells are resistant to acute free fatty acid-induced dysfunction. Corresponding to these phenotypes, Atf4-deficient beta-cells down-regulate genes involved in protein translation, reducing beta-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 although Atf4 activation is required for beta-cell identity and function under high glucose, this activation induces beta-cell failure in the presence of high levels of free fatty acids. An implication is that different branches of Atf4 activity could be manipulated for protecting beta-cells from metabolic stress-induced failure