Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes

Both bone mass and serum leptin levels are increased in obesity. Because os teoblasts and adipocytes arise from a common precursor in bone marrow, we a ssessed the effects of human recombinant leptin on a conditionally immortal ized human marrow stromal cell line, hMS2-12, with the potential to differe ntiate to either the osteoblast or adipocyte phenotypes. By RT-PCR and West ern immunoblot analysis, the hMS2-12 cells expressed messenger RNA (mRNA) a nd protein for the leptin receptor. Leptin did not affect hMS2-12 cell prol iferation, but resulted in dose- and time-dependent increases in mRNA and p rotein levels of alkaline phosphatase, type I collagen, and osteocalcin, an d in a 59% increase in mineralized matrix. Leptin increased mRNA levels of lipoprotein lipase at 3 days, but decreased mRNA levels of adipsin and lept in at 9 days and decreased lipid droplet formation by 50%. Leptin did not a ffect the expression of Cbfa1 or peroxisome proliferator-activated receptor -gamma(2), transcription factors involved in commitment to the osteoblast a nd adipocyte pathways, respectively. Thus, leptin acts on human marrow stro mal cells to enhance osteoblast differentiation and to inhibit adipocyte di fferentiation. Our data support the hypothesis that leptin is a previously unrecognized, physiological regulator of these two differentiation pathways , acting primarily on maturation of stromal cells into both lineages.