Cell Reports (Jun 2014)

Inhibition of Endothelial p53 Improves Metabolic Abnormalities Related to Dietary Obesity

  • Masataka Yokoyama,
  • Sho Okada,
  • Atsushi Nakagomi,
  • Junji Moriya,
  • Ippei Shimizu,
  • Aika Nojima,
  • Yohko Yoshida,
  • Harumi Ichimiya,
  • Naomi Kamimura,
  • Yoshio Kobayashi,
  • Shigeo Ohta,
  • Marcus Fruttiger,
  • Guillermina Lozano,
  • Tohru Minamino

DOI
https://doi.org/10.1016/j.celrep.2014.04.046
Journal volume & issue
Vol. 7, no. 5
pp. 1691 – 1703

Abstract

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Accumulating evidence has suggested a role for p53 activation in various age-associated conditions. Here, we identified a crucial role of endothelial p53 activation in the regulation of glucose homeostasis. Endothelial expression of p53 was markedly upregulated when mice were fed a high-calorie diet. Disruption of endothelial p53 activation improved dietary inactivation of endothelial nitric oxide synthase that upregulated the expression of peroxisome proliferator-activated receptor-γ coactivator-1α in skeletal muscle, thereby increasing mitochondrial biogenesis and oxygen consumption. Mice with endothelial cell-specific p53 deficiency fed a high-calorie diet showed improvement of insulin sensitivity and less fat accumulation, compared with control littermates. Conversely, upregulation of endothelial p53 caused metabolic abnormalities. These results indicate that inhibition of endothelial p53 could be a novel therapeutic target to block the vicious cycle of cardiovascular and metabolic abnormalities associated with obesity.