RXR antagonism induces G0 /G1 cell cycle arrest and ameliorates obesity by up-regulating the p53-p21(Cip1) pathway in adipocytes.

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 G0/G1 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:G0 + G1 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 G0 /G1 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 G0/G1 cell cycle arrest and the inhibition of cellular hypertrophy of adipocytes.

• Authors: 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
• Journal: The Journal of pathology (J Pathol) Vol. 226 Issue 5 Pg. 784-95 (Apr 2012) ISSN: 1096-9896 [Electronic] England
• PMID: 21956786 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chemical References

• Anti-Obesity Agents
• Benzoates
• Biphenyl Compounds
• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Hypoglycemic Agents
• PPAR gamma
• Retinoid X Receptors
• TP53 protein, human
• Thiazolidinediones
• Tumor Suppressor Protein p53
• diazepinylbenzoic acid
• Pioglitazone

Topics

• Adipocytes (drug effects, metabolism, pathology)
• Animals
• Anti-Obesity Agents (pharmacology)
• Benzoates (pharmacology)
• Biphenyl Compounds (pharmacology)
• Cell Proliferation (drug effects)
• Cell Size (drug effects)
• Cells, Cultured
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Diabetes Mellitus, Type 2 (drug therapy, metabolism, pathology)
• Disease Models, Animal
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Hypertrophy
• Hypoglycemic Agents (pharmacology)
• Kidney Glomerulus (drug effects, metabolism, pathology)
• Male
• Obesity (drug therapy, genetics, metabolism, pathology)
• PPAR gamma (drug effects, metabolism)
• Pioglitazone
• RNA Interference
• Rats
• Rats, Inbred OLETF
• Resting Phase, Cell Cycle (drug effects)
• Retinoid X Receptors (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Thiazolidinediones (pharmacology)
• Time Factors
• Transfection
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Up-Regulation