In addition to hormones and the sympathetic nervous system, specific nutrients may regulate leptin mRNA expression and adipose tissue metabolism. However, little is known regarding the effect of nutrients on leptin mRNA expression. Retinoic acid (RA) is a ligand of some nuclear receptors and previous reports have demonstrated contradictive effects on plasma leptin levels. Thus, we examined the effect of RA on expression of leptin in adipocytes of murine and human origin. After 48 h incubation of murine 3T3-L1 adipocytes with 1 and 10 μM all-trans RA, the expression of leptin mRNA was reduced by 56% and 65%, respectively, whereas the secretion of leptin was reduced by 38% and 77%, respectively. In human adipose tissue explants, 1 μM all-trans RA reduced leptin mRNA expression levels by 55% and leptin secretion by 25% after 24 h incubation. We observed an increased mRNA expression level of the transcription factors peroxisomal proliferator activated receptor γ (PPARγ), retinoid X receptor α (RXRα), and RA receptor α (RARα) in 3T3-L1 cells, whereas the mRNA level of these transcription factors was unchanged in human adipose tissue explants after incubation with RA. In two other leptin-expressing cell systems, the human placental throphoblast cell line BeWo and normal human primary osteoblasts, there was no effect of RA on leptin mRNA expression, but leptin secretion was reduced by 64% after 24 h incubation with 10 μM all-trans RA in BeWo cells. In conclusion, all-trans RA reduced both expression and secretion of leptin in human and rodent adipose tissue. In human BeWo cells or primary osteoblasts, leptin mRNA expression levels was not changed by all-trans RA, indicating a tissue-specific regulation of leptin mRNA expression by all-trans RA. © 2004 Wiley-Liss, Inc.