This study shows that leptin induced a rapid phosphorylation of p42/44 mitogen-activated protein kinase, an enhancement of both NF-B DNA binding and transcriptional activities, and a concentration-dependent increase of HT-29 cell proliferation. These effects are consistent with the presence of leptin receptors on cell membranes. The leptin induction of cell growth was associated with an increase of cell population in S and G 2 /M phase compared with control cells found in G 0 /G 1 phase of the cell cycle. Moreover, cyclin D1 immunoreactivity was enhanced in leptin-treated HT-29 cells and this increase was essentially associated with cell population in G 0 /G 1 phase. On the other hand, we observed that sodium butyrate inhibited cell proliferation by blocking HT-29 cells in G 0 /G 1 phase of the cell cycle. Interestingly, at physiological concentration, leptin prevented sodium butyrate-induced morphological nucleus changes, DNA laddering and suppressed butyrate-induced cell cycle arrest. This anti-apoptotic effect of leptin was associated with HT-29 cell proliferation and activation NF-B pathways. However, the phosphorylation of p42/44 MAP kinase in response to leptin was reduced in butyrate-treated cells. These data demonstrated that leptin is a potent mitogenic factor for intestinal epithelial cells through the MAP kinase and NF-B pathways. They also showed, for the first time, that leptin promotes colon cancer HT-29 cell survival upon butyrate challenge by counteracting the apoptotic programs initiated by this short chain fatty acid probably through the NF-B pathways. Although further studies are required to unravel the precise mechanism, these data may have significance in the pathogenesis of colorectal cancer and ulcerative colitis diseases.Leptin, the protein product encoded by the ob gene, is a 16-kDa circulating hormone produced primarily by adipose tissue and is a multifunctional hormone that regulates body weight homeostasis, neuroendocrine function, fertility, immune function, and angiogenesis (1-4). The biological actions of leptin on target tissues are carried out through interaction with its specific receptors, Ob-R. The leptin receptor (Ob-R) 1 is a member of the gp130 family of cytokine receptors (5), which occurs in several receptor variants (Ob-Ra through Ob-Rf) that are generated by alternative splicing of the db leptin receptor gene. These isoforms share the same extracellular domain but differ in the length of the transmembrane/cytoplasmic (6, 7). The long Ob-Rb subtype (Ob-R L ) appears as the functional, signal-transducing isoform, responsible for the action of leptin (8). The long isoform, Ob-Rb, can activate the signal transducers and activators of transcription (STAT) pathways, whereas both Ob-Rb and the short isoform (Ob-Ra) can transduce signals through insulin receptor substrates and through mitogenactivated protein kinase-(MAP kinase) dependent pathways (for review, see Ref. 9). Although, it is currently believed that leptin action is largely mediated by the central nervous system, t...