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bioRxiv · 10.1101/2024.06.28.601249

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

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.
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Abstract

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. HighlightsO_LIAtf4 is dispensable in {beta}-cells in young mice C_LIO_LIAtf4 protects {beta}-cells under high glucose C_LIO_LIAtf4 exacerbate fatty acid-induced {beta}-cell defects C_LIO_LIAtf4 activates translation but depresses lipid-metabolism C_LI

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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.. 2024-07-02. 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. https://doi.org/10.1101/2024.06.28.601249

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