RXR antagonism induces G 0/G 1 cell cycle arrest and ameliorates obesity by up-regulating the p53-p21 Cip1 pathway in adipocytes

Atsuko Nakatsuka, Jun Wada, Kazuyuki Hida, Aya Hida, Jun Eguchi, Sanae Teshigawara, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Daisuke Ogawa, Hiroyuki Kagechika, Hirofumi Makino

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

The peroxisome proliferator activated receptor-γ (PPARγ) agonist, pioglitazone (PIO), exerts anti-diabetic properties associated with increased fat mass, whereas the retinoid X receptor (RXR) antagonist HX531 demonstrates anti-obesity and anti-diabetic effects with reduced body weight and fat pad mass. The cell cycle abnormality in adipocytes has not been well-investigated in obesity or during treatment with modulators of nuclear receptors. We therefore investigated cell size and cell cycle distributions of adipocytes in vivo and examined the expression of cell cycle regulators in cultured human visceral preadipocytes. The cell size distribution and cell cycle analyses of in vivo adipocytes derived from OLETF rats demonstrated that HX531 brought about G 0/G 1 cell cycle arrest associated with the inhibition of cellular hypertrophy, which resulted in the reduction of fat pad mass. In contrast, PIO promoted proliferation activities associated with the increase in M + late M:G 0 + G 1 ratio and the appearance of both small and hypertrophied adipocytes. In cultured human visceral preadipocytes HX531 up-regulated cell cycle regulators, p53, p21 Cip1, cyclin D1, Fbxw7 and Skp2, which are known contributors towards G 0/G 1 cell cycle arrest. The knockdown of p53 with a shRNA lentivirus reversed the HX531-induced up-regulation of p21 Cip1, which is one of the major p53-effector molecules. We conclude that HX531 exerts anti-obesity and anti-diabetes properties by up-regulating the p53-p21 Cip1 pathway, resulting in G 0/G 1 cell cycle arrest and the inhibition of cellular hypertrophy of adipocytes.

Original languageEnglish
Pages (from-to)784-795
Number of pages12
JournalJournal of Pathology
Volume226
Issue number5
DOIs
Publication statusPublished - Apr 2012

    Fingerprint

Keywords

  • Cell cycle
  • Nuclear receptors
  • Obesity
  • p21
  • p53
  • RXR

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this