FTO Inhibits Insulin Secretion and Promotes NF-κB Activation through Positively Regulating ROS Production in Pancreatic β cells

PLoS One. 2015 May 27;10(5):e0127705. doi: 10.1371/journal.pone.0127705. eCollection 2015.


FTO (Fat mass and obesity-associated) is associated with increased risk of obesity and type 2 diabetes incurrence. Pancreas islet β cells dysfunction and insulin resistance are major causes of type 2 diabetes. However, whether FTO plays an important functional role in pancreatic β cells as well as the related molecular mechanism is still unclear. In the present study, the tissue expression profile of FTO was firstly determined using quantitative PCR and western blot. FTO is widely expressed in various tissues and presented with relative high expression in pancreas tissue, especially in endocrine pancreas. FTO overexpression in MIN6 cells achieved by lentivirus delivery significantly inhibits insulin secretion in the presence of glucose stimulus as well as KCl. FTO silence has no effect on insulin secretion of MIN6 cells. However, FTO overexpression doesn't affect the transcription of insulin gene. Furthermore, reactive oxygen species (ROS) production and NF-κB activation are significantly promoted by FTO overexpression. Inhibition of intracellular ROS production by N-acetyl-L-cysteine (NAC) can alleviate NF-κB activation and restore the insulin secretion mediated by FTO overexpression. A whole transcript-microarray is employed to analyze the differential gene expression mediated by FTO overexpression. The genes which are modulated by FTO are involved in many important biological pathways such as G-protein coupled receptor signaling and NF-κB signaling. Therefore, our study indicates that FTO may contribute to pancreas islet β cells dysfunction and the inhibition of FTO activity is a potential target for the treatment of diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / metabolism
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • Animals
  • Diabetes Mellitus, Type 2 / metabolism
  • Gene Expression Regulation / physiology
  • Glucose / metabolism
  • Insulin / metabolism*
  • Insulin Resistance / physiology
  • Insulin-Secreting Cells / metabolism*
  • Islets of Langerhans / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mixed Function Oxygenases / metabolism*
  • NF-kappa B / metabolism*
  • Oxo-Acid-Lyases / metabolism*
  • Reactive Oxygen Species / metabolism*
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction / physiology


  • Insulin
  • NF-kappa B
  • Reactive Oxygen Species
  • Receptors, G-Protein-Coupled
  • Mixed Function Oxygenases
  • FTO protein, mouse
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • Oxo-Acid-Lyases
  • Glucose
  • Acetylcysteine

Grants and funding

This study was supported by grants from the National Natural Science Foundation of China (81100578), the Specialized Research Fund for the Doctoral Program of Higher Education (20113234120011), and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions. All the grants support the study design, data collection and decision to publish.