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Nuclear Factor Y in Male Mouse pancreatic β-cells Plays a Crucial Role in Glucose Homeostasis by Regulating β-Cell Mass and Insulin Secretion

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posted on 13.05.2021, 09:20 by Yin Liu, Siyuan He, Ruixue Zhou, Xueping Zhang, Shanshan Yang, Dan Deng, Caixia Zhang, Xiaoqian Yu, Yulong Chen, Zhiguang Su
Pancreatic β-cell mass and insulin secretion are determined by the dynamic change of transcription factor expression levels in response to altered metabolic demand. Nuclear factor-Y (NF-Y) is an evolutionarily conserved transcription factor playing critical roles in multiple cellular processes. However, the physiological role of NF-Y in pancreatic β-cells is poorly understood. The present study was undertaken in a conditional knockout of Nf-ya specifically in pancreatic β-cells (Nf-ya βKO) to define the essential physiological role of NF-Y in β-cells. Nf-ya βKO mice exhibited glucose intolerance without changes in insulin sensitivity. Reduced β-cell proliferation resulting in decreased β-cell mass was observed in these mice, which was associated with disturbed actin cytoskeleton. NF-Y-deficient β-cells also exhibited impaired insulin secretion with a reduced Ca2+ influx in response to glucose, which was associated an inefficient glucose uptake into β-cells due to a decreased expression of glucose transporter 2 and a reduction in ATP production resulting from the disruption of mitochondrial integrity. This study is the first to show that NF-Y is critical for pancreatic islets homeostasis and function through regulation in β-cell proliferation, glucose uptake into β-cells, and mitochondrial energy metabolism. Modulating NF-Y expression in β-cells may therefore offer an attractive approach for therapeutic intervention.

Funding

This study was supported by the National Natural Science Foundation of China (No. 81770814), the Sichuan Province Science and Technology Support Program (2020YF0192), the National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (Z20201010), and the Graduate Student`s Research and Innovation Fund of Sichuan University (2018YJSY118).

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