Yagan, M.; Najam, S.; Hu, R.; Wang, Y.; DAdi, P.; Xu, Y.; Simmons, A. J.; Stein, R.; Adams, C. M.; Jacobson, D. J.; Lau, K.; Liu, Q.; Gu, G.

Glucolipotoxicity, caused by combined hyperglycemia and hyperlipidemia, results in beta-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 Atf4 expression in beta-cells is dispensable for glucose homeostasis in young mice, but it is required for beta-cell function during aging and under obesity-related metabolic stress. Henceforth, aged Atf4-deficient beta-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, 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 Atf4 activation is required for beta-cell identity and function under high glucose, but this paradoxically induces beta-cell failure in the presence of high levels of free fatty acids. Different branches of Atf4 activity could be manipulated for protecting beta-cells from metabolic stress-induced failure.