Meltrin is a member of the metalloprotease-disintegrin (ADAM) family. In this paper, we demonstrate that Meltrin is involved in the development of white adipose tissue. Compared with wild-type mice, Meltrin - mice displayed moderate resistance to weight gain induced by a high-fat diet mainly because of an impaired increase in the number of adipocytes. There was no obvious difference in adipocyte size between wild-type and Meltrin -/- mice, suggesting normal maturation of adipocytes of the latter under a high-fat diet. Embryonic fibroblasts and the stromal-vascular cells lacking Meltrin exhibited impaired cell proliferation upon adipogenic stimulation, which was accompanied by moderate defects in adipose differentiation. Addition of culture medium conditioned with wild-type cells in an early phase of adipose differentiation did not restore the defects in the Meltrin -/- cells. These results uncover the involvement of Meltrin in the development of obesity and in adipogenic cell proliferation.