NF-kappa B p65 serine 467 phosphorylation sensitizes mice to weight gain and TNF alpha-or diet-induced inflammation

Tabea Riedlinger, Marleen B Dommerholt, Tobias Wijshake, Janine K Kruit, Nicolette Huijkman, Daphne Dekker, Mirjam Koster, Niels Kloosterhuis, Debby P Y Koonen, Alain de Bruin, Darren Baker, Marten H Hofker, Jan van Deursen, Johan W Jonker, M Lienhard Schmitz, Bart van de Sluis*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Scopus)

Abstract

The NF-kappa B family of transcription factors is essential for an effective immune response, but also controls cell metabolism, proliferation and apoptosis. Its broad relevance and the high connectivity to diverse signaling pathways require a tight control of NF-kappa B activity. To investigate the control of NF-kappa B activity by phosphorylation of the NF-kappa B p65 subunit, we generated a knock-in mouse model in which serine 467 (the mouse homolog of human p65 serine 468) was replaced with a non-phosphorylatable alanine (S467A). This substitution caused reduced p65 protein synthesis and diminished TNF alpha-induced expression of a selected group of NF-kappa B dependent genes. Intriguingly, high-fat fed S467A mice displayed increased locomotor activity and energy expenditure, which coincided with a reduced body weight gain. Although glucose metabolism or insulin sensitivity was not improved, diet-induced liver inflammation was diminished in S467A mice. Altogether, this study demonstrates that phosphorylation of p65 serine 467 augment NF-kappa B activity and exacerbates various deleterious effects of overnutrition in mice.

Original languageEnglish
Pages (from-to)1785-1798
Number of pages14
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1864
Issue number10
Early online date16-Jul-2017
DOIs
Publication statusPublished - Oct-2017

Keywords

  • Metabolism
  • Inflammation
  • Gene expression
  • Aging Insulin
  • Obesity
  • INDUCED INSULIN-RESISTANCE
  • T-CELL COSTIMULATION
  • IKK-EPSILON
  • IMMUNE-RESPONSE
  • KINASE-BETA
  • LIVER
  • DISEASE
  • OBESITY
  • METABOLISM
  • ACTIVATION

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