Hyperproduction of IL-6 caused by aberrant TDP-43 overexpression in high-fat diet-induced obese mice

FEBS Lett. 2015 Jul 8;589(15):1825-31. doi: 10.1016/j.febslet.2015.05.040. Epub 2015 May 30.

Abstract

Inclusion of Tat-activating regulatory DNA-binding protein-43 (TDP-43) due to hyperphosphorylation or hyperubiquitination is a cause of neurodegenerative disease. Cellular TDP-43 expression is tightly controlled through a negative feedback loop involving its mRNA. Recently, we reported that the TDP-43-mediated sub-nuclear body is an essential site of interleukin-6 (IL-6) pre-mRNA processing. Here we show that mice fed on a high-fat diet exhibit increased TDP-43 expression in the liver and adipose tissue with a prominent increase in IL-6. TDP-43 depletion in vivo reduces IL-6 production in the liver. Overexpression or depletion of TDP-43 in pre-adipose and adipose cells causes reciprocal alteration of IL-6 expression and RNA processing. Our findings provide evidence for a link between homeostasis of TDP-43 expression and the risk of developing obesity.

Keywords: High-fat diet (HFD) mice; Interleukin-6; Obesity; Pre-mRNA processing; Tat-activating regulatory DNA-binding protein-43 (TDP-43).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Animals
  • Base Sequence
  • DNA Primers
  • DNA-Binding Proteins / metabolism*
  • Diet, High-Fat*
  • Enzyme-Linked Immunosorbent Assay
  • HEK293 Cells
  • Humans
  • Interleukin-6 / biosynthesis*
  • Interleukin-6 / genetics
  • Mice
  • Obesity / etiology
  • Obesity / metabolism*
  • Phosphorylation
  • RNA Precursors / genetics
  • RNA Processing, Post-Transcriptional
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction

Substances

  • DNA Primers
  • DNA-Binding Proteins
  • Interleukin-6
  • RNA Precursors
  • RNA, Messenger
  • TDP-43 protein, mouse