Recently, we have determined the role of leptin as a keratinocyte mitogen in vitro and during skin repair in vivo. In this study, we assessed leptin-stimulated signal transduction in the human keratinocyte cell line HaCaT and the murine keratinocyte cell line PAM 212. HaCaT keratinocytes were characterized by a constitutive phosphorylation of janus kinase (JAK)-2. By contrast, PAM 212 keratinocytes responded to leptin with a rapid phosphorylation of JAK-2. However, we could determine a cytoplasmic activation of signal transducer and activator of transcription (STAT)-3 by phosphorylation of tyrosine 705 (Y705) within minutes only upon leptin stimulation in both keratinocyte cell lines. Subsequently, STAT-3 translocated to the nucleus where serine 727 (S727) was phosphorylated, establishing a transcriptionally active STAT-3 transcription factor. In a model of cutaneous wound healing, treatment of leptin-deficient obeselobese (oblob) mice strongly augmented phosphorylation of STAT-3 (Y705) in wound keratinocytes also in vivo. (C) 2003 Elsevier Science (USA). All rights reserved.