Dalong Song1, Qi Yang1, Xiuli Jiang1, Aijing Shan1, Jingminjie Nan1, Ying Lei1, He Ji1, Wei Di1, Tianxiao Yang1, Tiange Wang1, Weiqing Wang1, Guang Ning1, Yanan Cao2. 1. Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Centre for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai Key Laboratory for Endocrine Tumors, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 2. Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Centre for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai Key Laboratory for Endocrine Tumors, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Research Center for Translational Medicine, National Key Scientific Infrastructure for Translational Medicine (Shanghai), Shanghai Jiao Tong University, Shanghai, China. Electronic address: caoyanan@vip.sina.com.
Abstract
BACKGROUND: The transcription factor YY1 is an important regulator for metabolic homeostasis. Activating mutations in YY1 lead to tumorigenesis of pancreatic β-cells, however, the physiological functions of YY1 in β-cells are still unknown. Here, we investigated the effects of YY1 ablation on insulin secretion and glucose metabolism. METHODS: We established two models of β-cell-specific YY1 knockout mice. The glucose metabolic phenotypes, β-cell mass and β-cell functions were analyzed in the mouse models. Transmission electron microscopy was used to detect the ultrastructure of β-cells. The flow cytometry analysis, measurement of OCR and ROS were performed to investigate the mitochondrial function. Histological analysis, quantitative PCR and ChIP were performed to analyze the target genes of YY1 in β-cells. RESULTS: Our results showed that loss of YY1 resulted in reduction of insulin production, β-cell mass and glucose tolerance in mice. Ablation of YY1 led to defective ATP production and mitochondrial ROS accumulation in pancreatic β-cells. The inactivation of YY1 impaired the activity of mitochondrial oxidative phosphorylation, induced mitochondrial dysfunction and diabetes in mouse models. CONCLUSION: Our findings demonstrate that the transcriptional activity of YY1 is essential for the maintenance of mitochondrial functions and insulin secretion in β-cells.
BACKGROUND: The transcription factor YY1 is an important regulator for metabolic homeostasis. Activating mutations in YY1 lead to tumorigenesis of pancreatic β-cells, however, the physiological functions of YY1 in β-cells are still unknown. Here, we investigated the effects of YY1 ablation on insulin secretion and glucose metabolism. METHODS: We established two models of β-cell-specific YY1 knockout mice. The glucose metabolic phenotypes, β-cell mass and β-cell functions were analyzed in the mouse models. Transmission electron microscopy was used to detect the ultrastructure of β-cells. The flow cytometry analysis, measurement of OCR and ROS were performed to investigate the mitochondrial function. Histological analysis, quantitative PCR and ChIP were performed to analyze the target genes of YY1 in β-cells. RESULTS: Our results showed that loss of YY1 resulted in reduction of insulin production, β-cell mass and glucose tolerance in mice. Ablation of YY1 led to defective ATP production and mitochondrial ROS accumulation in pancreatic β-cells. The inactivation of YY1 impaired the activity of mitochondrial oxidative phosphorylation, induced mitochondrial dysfunction and diabetes in mouse models. CONCLUSION: Our findings demonstrate that the transcriptional activity of YY1 is essential for the maintenance of mitochondrial functions and insulin secretion in β-cells.
Authors: Di Liu; Kevin Y Yang; Vicken W Chan; Wenchu Ye; Charing C N Chong; Chi Chiu Wang; Huating Wang; Bin Zhou; Kenneth K Y Cheng; Kathy O Lui Journal: Diabetes Date: 2022-05-01 Impact factor: 9.461