White adipose tissue (WAT) is intimately involved in the regulation of immunity and inflammation. We reported that human mesenteric preadipocytes express the substance P (SP)-mediated neurokinin-1 receptor (NK-1R), which signals proinflammatory responses. Here we tested the hypothesis that SP promotes proliferation and survival of human mesenteric preadipocytes and investigated responsible mechanism(s). Preadipocytes were isolated from mesenteric fat biopsies during gastric bypass surgery. Proliferative and anti-apoptotic responses were delineated in MTS, BrdU, caspase-3, and TUNEL assays, as well as Western immunoanalysis. SP (10^-7M) increased mesenteric preadipocyte cell viability (MTS) and proliferation (BrdU) and, time-dependently (15-30 min), induced Akt, EGFR, IGFR, 53 integrin, PI3 kinase and PKC- phosphorylation. Further, pharmacologic antagonism of Akt and PKC-theta activation significantly attenuated SP-induced preadipocyte proliferation. Exposure of preadipocytes to the pro-apoptotic Fas ligand (FasL, 100 µM) resulted in nuclear DNA fragmentation (TUNEL assay), as well as increased cleaved PARP, cleaved caspase-7, and caspase-3 expression. Co-treatment with SP almost completely abolished these responses in a NK-1R - dependent fashion. SP (10^-7M) also time-dependently stimulated expression of 4E-BP1 and phosphorylation of p70 S6 kinase, which increase protein translation efficiency. SP increases preadipocyte viability, reduces apoptosis, and stimulates proliferation, possibly via cell cycle upregulation and increased protein translation efficiency. SP-induced proliferative and anti-apoptotic pathways in fat depots may contribute to development of the creeping fat and inflammation characteristic of Crohn's Disease.