NF-κB p65 serine 467 phosphorylation sensitizes mice to weight gain and TNFα-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 J Baker, Marten H. Hofker, Jan Van Deursen, Johan W. Jonker, M. Lienhard Schmitz, Bart van de Sluis

Research output: Contribution to journalArticle

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Abstract

The NF-κB 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-κB activity. To investigate the control of NF-κB activity by phosphorylation of the NF-κB 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 TNFα-induced expression of a selected group of NF-κB-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-κB activity and exacerbates various deleterious effects of overnutrition in mice.

Original languageEnglish (US)
Pages (from-to)1785-1798
Number of pages14
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1864
Issue number10
DOIs
StatePublished - Oct 1 2017

Fingerprint

Serine
Weight Gain
Phosphorylation
Diet
Inflammation
Overnutrition
Locomotion
Alanine
Energy Metabolism
Insulin Resistance
Transcription Factors
Fats
Body Weight
Cell Proliferation
Apoptosis
Glucose
Liver
Genes
Proteins

Keywords

  • Aging
  • Gene expression
  • Inflammation
  • Insulin
  • Metabolism
  • Obesity

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Riedlinger, T., Dommerholt, M. B., Wijshake, T., Kruit, J. K., Huijkman, N., Dekker, D., ... van de Sluis, B. (2017). NF-κB p65 serine 467 phosphorylation sensitizes mice to weight gain and TNFα-or diet-induced inflammation. Biochimica et Biophysica Acta - Molecular Cell Research, 1864(10), 1785-1798. https://doi.org/10.1016/j.bbamcr.2017.07.005

NF-κB p65 serine 467 phosphorylation sensitizes mice to weight gain and TNFα-or diet-induced inflammation. / Riedlinger, Tabea; Dommerholt, Marleen B.; Wijshake, Tobias; Kruit, Janine K.; Huijkman, Nicolette; Dekker, Daphne; Koster, Mirjam; Kloosterhuis, Niels; Koonen, Debby P.Y.; de Bruin, Alain; Baker, Darren J; Hofker, Marten H.; Van Deursen, Jan; Jonker, Johan W.; Schmitz, M. Lienhard; van de Sluis, Bart.

In: Biochimica et Biophysica Acta - Molecular Cell Research, Vol. 1864, No. 10, 01.10.2017, p. 1785-1798.

Research output: Contribution to journalArticle

Riedlinger, T, Dommerholt, MB, Wijshake, T, Kruit, JK, Huijkman, N, Dekker, D, Koster, M, Kloosterhuis, N, Koonen, DPY, de Bruin, A, Baker, DJ, Hofker, MH, Van Deursen, J, Jonker, JW, Schmitz, ML & van de Sluis, B 2017, 'NF-κB p65 serine 467 phosphorylation sensitizes mice to weight gain and TNFα-or diet-induced inflammation', Biochimica et Biophysica Acta - Molecular Cell Research, vol. 1864, no. 10, pp. 1785-1798. https://doi.org/10.1016/j.bbamcr.2017.07.005
Riedlinger, Tabea ; Dommerholt, Marleen B. ; Wijshake, Tobias ; Kruit, Janine K. ; Huijkman, Nicolette ; Dekker, Daphne ; Koster, Mirjam ; Kloosterhuis, Niels ; Koonen, Debby P.Y. ; de Bruin, Alain ; Baker, Darren J ; Hofker, Marten H. ; Van Deursen, Jan ; Jonker, Johan W. ; Schmitz, M. Lienhard ; van de Sluis, Bart. / NF-κB p65 serine 467 phosphorylation sensitizes mice to weight gain and TNFα-or diet-induced inflammation. In: Biochimica et Biophysica Acta - Molecular Cell Research. 2017 ; Vol. 1864, No. 10. pp. 1785-1798.
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