Oxygen is the most important factor for the appropriate regulation of multiple energy homeostasis and cell differentiation. Although hypoxia-induced signaling cascades have been intensively studied, the molecular mechanism by which hypoxic signals suppress adipocyte differentiation is unclear. Here, we demonstrated that repression of adipocyte differentiation by hypoxia and HIF1 alpha-or Stra13-overexpression was not associated with HDACs. Furthermore, HDACs did not affect inhibitory effect of Stra13 on PPAR gamma promoter activity, although the hypoxia-induced suppression of adipogenesis was accompanied with reduced acetylation of histone H3 and H4 at the PPAR gamma promoter. Instead, we revealed that hypoxic circumstances biphasically activated AMPK and concomitantly blocked clonal expansion of preadipocytes, which is an indispensable step for early phase of adipocyte differentiation. Taken together, these results suggest that hypoxic condition attenuates adipocyte differentiation by inhibition of PPAR gamma expression in a HDAC-independent manner and by activation of AMPK which impairs clonal expansion phase. (c) 2005 Elsevier Inc. All rights reserved.