FTO Affects Hippocampal Function by Regulation of BDNF Processing

PLoS One. 2019 Feb 7;14(2):e0211937. doi: 10.1371/journal.pone.0211937. eCollection 2019.

Abstract

Initially, the function of the fat mass and obesity associated (Fto) gene seemed to be primarily the regulation of the body weight. Here we show that loss of Fto results in a hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis. In consequence, Fto-/- mice display an anxiety-like behavior and impairments in working memory. Furthermore, differentiation of neurons is affected in the hippocampus. As a cause of these impairments we identified a processing defect of the neurotrophin BDNF which is most likely the result of a reduced expression of MMP-9. Therefore, we propose FTO as a possible new target to develop novel approaches for the treatment of diseases associated with hippocampal disorders. In parallel, we also would like to make the point that any anti-obesity therapy via blocking FTO function can have negative effects on the proper function of the hippocampus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / metabolism*
  • Animals
  • Anxiety / genetics
  • Anxiety / metabolism
  • Anxiety / pathology
  • Behavior, Animal
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Hippocampus / metabolism*
  • Hippocampus / pathology
  • Hypothalamo-Hypophyseal System / metabolism
  • Hypothalamo-Hypophyseal System / pathology
  • Matrix Metalloproteinase 9 / biosynthesis
  • Matrix Metalloproteinase 9 / genetics
  • Memory Disorders / genetics
  • Memory Disorders / metabolism
  • Memory Disorders / pathology
  • Memory, Short-Term
  • Mice
  • Mice, Knockout
  • Pituitary-Adrenal System / metabolism
  • Pituitary-Adrenal System / pathology
  • Protein Processing, Post-Translational*

Substances

  • Bdnf protein, mouse
  • Brain-Derived Neurotrophic Factor
  • FTO protein, mouse
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse

Grant support

The authors received no specific funding for this work.