TNF-α transiently induces endoplasmic reticulum stress and an incomplete unfolded protein response in the hypothalamus

Neuroscience. 2010 Nov 10;170(4):1035-44. doi: 10.1016/j.neuroscience.2010.08.013. Epub 2010 Aug 13.


In diet-induced obesity, hypothalamic inflammation is triggered as an outcome of prolonged exposure to dietary fats. Toll-like receptor 4 (TLR4) activation plays a central role in this process, inducing endoplasmic reticulum stress and activating inflammatory cytokine gene transcription. Although saturated fatty acids can induce endoplasmic reticulum stress in the hypothalamus, it is unknown whether inflammatory cytokines alone can activate this mechanism. Here, rats were treated with TNF-α or lyposaccharide (LPS) and endoplasmic reticulum stress and unfolded protein response were evaluated by immunoblot and polymerase chain reaction (PCR). Activation of TLR4 by LPS was capable of inducing a complete endoplasmic reticulum stress and unfolded protein response through the PERK/eIF2α and IRE1α/XBP1 pathways. Conversely, TNF-α, injected either locally or systemically, was unable to induce a complete program of unfolded protein response, although the activation of endoplasmic reticulum stress was achieved to a certain degree. Thus, in the hypothalamus, the isolated action of TNF-α is insufficient to produce the activation of a complete program of unfolded protein response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Endoplasmic Reticulum / physiology*
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism*
  • Hypothalamus / pathology
  • Inflammation / pathology
  • Lipopolysaccharides / pharmacology
  • Male
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Mice
  • Mice, Knockout
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / biosynthesis
  • Protein-Serine-Threonine Kinases / genetics
  • Rats
  • Rats, Wistar
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Tumor Necrosis Factor-alpha / physiology
  • Unfolded Protein Response*


  • Lipopolysaccharides
  • Membrane Proteins
  • Receptors, Tumor Necrosis Factor, Type I
  • Tnfrsf1a protein, mouse
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Ern2 protein, rat
  • Protein-Serine-Threonine Kinases