Nuclear Factor-Y in Mouse Pancreatic b-Cells Plays a Crucial Role in Glucose Homeostasis by Regulating b-Cell Mass and Insulin Secretion

Abstract

Pancreatic b-cell mass and insulin secretion are deter-mined 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 b-cells is poorly understood. The current study was undertaken in a conditional knockout of Nf-ya specifically in pancreatic b-cells (Nf-ya bKO) to define the essential physiological role of NF-Y in b-cells. Nf-ya bKO mice exhibited glucose intolerance without changes in insulin sensitivity. Reduced b-cell proliferation resulting in decreased b-cell mass was observed in these mice, which was associated with disturbed actin cyto-skeleton. NF-Y–deficient b-cells also exhibited impaired insulin secretion with a reduced Ca2+ influx in response to glucose, which was associated with an inefficient glucose uptake into b-cells due to a decreased expression of GLUT2 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 islet homeostasis and function through regulation in b-cell proliferation, glucose uptake into b-cells, and mitochon-drial energy metabolism. Modulating NF-Y expression in b-cells may therefore offer an attractive approach for therapeutic intervention.