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First published online July 13, 2004
doi: 10.1242/10.1242/jcs.01207

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Inhibition of adipocyte differentiation by mechanical stretching through ERK-mediated downregulation of PPAR₂

Department of Cellular and Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka-city, 422-8526, Japan

^* Author for correspondence (e-mail: nakyamk{at}ys7.u-shizuoka-ken.ac.jp)

Accepted 9 March 2004

This study investigated the effects of cyclic stretching on adipocyte differentiation of mouse preadipocyte 3T3-L1 cells. Confluent 3T3-L1 cells were treated with dexamethasone, 3-isobutyl-1-methylxanthine and insulin for 45 hours (induction period), followed by incubation with insulin for 9 additional days (maturation period). A transient burst of CCAAT/enhancer-binding protein (C/EBP) ß and C/EBP at an early stage (3 hours) and a delayed induction (45 hours) of C/EBP and PPAR₂ were sequentially provoked during the induction period. Application of cyclic stretching during the entire induction period or only during the final 15 hours of the induction period significantly retarded the induction of glycerol-3-phosphate dehydrogenase (GPDH) activity and the accumulation of intracellular triglycerides by the end of the maturation period. Cyclic stretching for the entire induction period, as well as that applied during the final 15 hours of the induction period, significantly reduced the expression of PPAR₂ mRNA, whereas reduction in the expression of C/EBP mRNA was only observed in response to stretching that had been applied during the entire induction period. The expression of C/EBP and C/EBPß mRNA did not change in response to stretching. Stretching induced the phosphorylation of extracellular-signal-regulated protein kinases 1 and 2 (ERK1/2), which are members of the mitogen-activated-protein kinase (MAPK) family, during the induction period. PD98,059, a MAPK/ERK kinase inhibitor, reversed the stretch-induced reduction of PPAR₂ at both mRNA and protein levels achieved during the induction period. PD98,059 also restored GPDH activity and lipid droplet accumulation. Furthermore, the differentiation inhibited by the stretching was also restored by synthetic PPAR ligand. Collectively, these results suggest that the inhibition of adipocyte differentiation in response to stretching is mainly attributable to the reduced expression of PPAR₂, which is mediated by activation of the ERK/MAPK system.

Key words: Adipocyte differentiation, Stretching, PPAR, ERK, Mechanotransduction

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