Tài liệu Báo cáo khoa học: 3T3-L1 adipocyte apoptosis induced by thiazolidinediones is peroxisome

3T3-L1 adipocyte apoptosis induced by thiazolidinediones

is peroxisome proliferator-activated receptor-c-dependent

and mediated by the caspase-3-dependent apoptotic

pathway

Yuanyuan Xiao, Taichang Yuan, Wenqi Yao and Kan Liao

State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese

Academy of Sciences, Shanghai, China

Introduction

To date, studies of adipocyte physiology have primarily

focused on adipogenesis [1–3]. The interaction between

extracellular signals and the transcriptional cascade dur￾ing adipogenesis has been well studied [4]. However,

owing to the remarkable ability of adipocytes to resist

apoptosis, adipocyte apoptosis is much less studied and

is poorly understood. Recently, evidence from several

in vivo and in vitro studies has indicated that apoptosis

is a significant factor in adipocyte depletion during

weight reduction [5–8]. In addition, an animal model of

adipocyte apoptosis has been developed as a tool for the

study of obesity-related diseases [9]. Adipocyte apopto￾sis is induced by some adipokines, such as leptin and

tumor necrosis factor-a [10–12]. Additionally, natural

Keywords

3T3-L1 adipocyte; adipocyte apoptosis;

Akt-1; PPARc; thiazolidinediones

Correspondence

K. Liao, Institute of Biochemistry and Cell

Biology, 320 Yueyang Road, Shanghai

200031, China

Fax: +86 21 54921011

Tel: +86 21 54921113

E-mail: [email protected]

(Received 11 March 2009, revised 16

November 2009, accepted 24 November

2009)

doi:10.1111/j.1742-4658.2009.07514.x

Although thiazolidinediones (TZDs) are potent promoters of adipogenesis

in the preadipocyte, they induce apoptosis in several other cell types,

such as cancer cells, endothelial cells and T-lymphocytes. In this study,

we investigated the proapoptotic effect of TZDs in mature 3T3-L1

adipocytes, which express high levels of the peroxisome proliferator-acti￾vated receptor-c (PPARc) protein. Apoptosis was induced in mature

3T3-L1 adipocytes by treatment with troglitazone, pioglitazone or prosta￾glandin J2, and could be blocked by the PPARc antagonist GW9662.

Treatment with PPARc agonists also decreased Akt-1 protein and phos￾phorylation levels without affecting phosphoinositide 3-kinase and PTEN.

Further analysis indicated that in troglitazone-treated 3T3-L1 adipocytes,

Bad phosphorylation and Bcl-2 protein levels were reduced, and Bax

translocation to the mitochondria was increased. Subsequently, cyto￾chrome c release and caspase-3 cleavage were observed. TZD-induced

adipocyte apoptosis could be blocked by the caspase-3 inhibitor

Ac-DEVD-CHO or by overexpression of Bcl2. In cultured rat primary

adipocytes, similar apoptosis-inducing effects of troglitazone were also

observed. Thus, TZDs promote apoptosis in adipocytes through a

PPARc-dependent pathway. This apoptosis is mediated by the inhibition

of Akt-1, which decreases Bad phosphorylation and activates the mito￾chondrial apoptotic pathway.

Abbreviations

AO, acridine orange; EB, ethidium bromide; FACS, fluorescence-activated cell sorting; pBad, phosphorylated Bad; pAkt-1, phosphorylated

Akt-1; PGJ2, 15-deoxy-D12,14-prostaglandin J; 2PI, propidium iodide; PI3K, phosphoinositide 3-kinase; PPARc, peroxisome proliferator￾activated receptor-c; SD, standard deviation; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; TZD, thiazolidinedione.

FEBS Journal 277 (2010) 687–696 ª 2009 The Authors Journal compilation ª 2009 FEBS 687