Skp2 Controls Adipocyte Proliferation during the Development of Obesity

Yasushi Matsuki,Masato Kasuga,Mitsuru Okada,Keiko Nakayama,Takehiro Nakamura,Keiichi I. Nakayama,Tamon Sakai,Hiroshi Sakaue,Ryuji Hiramatsu,Eijiro Watanabe

doi:10.1074/jbc.m608144200

Abstract

The increase in the mass of adipose tissue during the development of obesity can arise through an increase in cell size, an increase in cell number, or both. Here we show that long term maintenance of C57BL/6 mice on a high fat diet (for approximately 25 weeks) induces an initial increase in adipocyte size followed by an increase in adipocyte number in white adipose tissue. The latter effect was found to be accompanied by up-regulation of expression of the gene for the F-box protein Skp2 as well as by downregulation of the cyclin-dependent kinase inhibitor p27(Kip1), a principal target of the SCF(Skp2) ubiquitin ligase, in white adipose tissue. Ablation of Skp2 protected mice from the development of obesity induced either by a high fat diet or by the lethal yellow agouti (A(y)) mutation, and this protective action was due to inhibition of the increase in adipocyte number without an effect on adipocyte hypertrophy. The reduction in the number of adipocyte caused by Skp2 ablation also inhibited the development of obesity-related insulin resistance in the A(y) mutant mice, although the reduced number of beta cells and reduced level of insulin secretion in Skp2-deficient mice resulted in glucose intolerance. Our observations thus indicate that Skp2 controls adipocyte proliferation during the development of obesity.

Highlights

The number of adipocytes is thought to increase as a result of the proliferation of preadipocytes and their subsequent differentiation into mature adipocytes [4, 5]
The high fat diet induced a marked increase in the size of adipocytes (Fig. 1C) but had no effect on adipocyte number (Fig. 1D) in epididymal white adipose tissue (WAT) after 10 weeks
The size of adipocytes did not differ significantly, between mice fed the high fat diet for 10 or 26 weeks. These results showed that an increase in adipocyte size precedes an increase in adipocyte number in C57BL/6 mice fed a high fat diet

Summary

Introduction

The number of adipocytes is thought to increase as a result of the proliferation of preadipocytes and their subsequent differentiation into mature adipocytes [4, 5]. Maintenance of C57BL/6 mice on the high fat diet for 10 weeks, which had no effect on adipocyte number, did not affect the abundance of p27Kip1 in epididymal WAT, as compared with that apparent in animals fed the normal diet (Fig. 1E).

Results

Conclusion