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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

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posted on 2025-02-03, 17:47 authored by Mahircan Yagan, Sadia Najam, Ruiying Hu, Yu Wang, Mathew Dickerson, Prasanna Dadi, Yanwen Xu, Alan J. Simmons, Roland Stein, Christopher M. Adams, David A. Jacobson, Ken S. Lau, Qi Liu, Guoqiang Gu

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.

Funding

This study is supported by NIDDK grants (DK125696 and DK128710 for GG, DK103831 and CA274367 for KSL, YX, and AJS). The imaging facility used is funded by (CA68485, DK20593, DK58404, DK59637, and EY08126).

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