Adult mice abundantly express neudesin, an extracellular heme-binding protein with neurotrophic activity, in white adipose tissues. At the early stage of adipocyte differentiation during adipogenesis, however, the expression of neudesin decreased transiently. Neudesin-hemin significantly suppressed adipogenesis in 3T3-L1 cells. The knockdown of neudesin by RNA interference markedly promoted adipogenesis in 3T3-L1 cells and decreased MAPK activation during adipocyte differentiation. The addition or knockdown of neudesin affected the expression of C/EBP alpha and PPAR gamma but not of C/EBP beta. These findings suggest that neudesin plays a critical role in the early stage of adipocyte differentiation in which C/EBP beta induces PPAR gamma and C/EBP alpha expressions, by controlling the MAPK pathway. (C) 2009 Elsevier Inc. All rights reserved.