NF-kappaB p65 serine 467 phosphorylation sensitizes mice to weight gain and TNFalpha-or diet-induced inflammation

Abstract

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