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Stromal-derived factor-1 (SDF-1) is a CXC chemokine produced by stromal and endothelial cells of numerous tissues composed of or and β isoforms. SDF-1 is an attract factor for numerous cells including hemopoietic progenitor cells, lymphocytes, and monocytes in vitro and is required for fetal B lymphopoiesis and myelopoeisis in vivo. SDF-1 is also chemotactic for endothelial cell lines. SDF-1 has been described in other important molecular and cellular functions such as organogenesis, regeneration and tumorigenesis, and development of cardiac and nervous tissues. In this study, we have identified a new role for SDF-1 in regulation of hepatic gluconeogenesis. We observed in isolated hepatocytes that SDF-1α and β could both inhibit glucose production via gluconeogenesis to a lesser extent than equimolar amounts of insulin. The inhibition of gluconeogenesis by SDF-1 is accompanied by a decreased expression of the glucose-6-phosphatase (G6Pase) gene. In defining the mechanism by which SDF-1 suppresses transcription of gluconeogenic genes, we found that SDF-1α and β could elevate phosphorylation of Akt, which is a necessary signaling component for insulin to block gluconeogenesis. These results indicate that SDF-1 can suppress hepatic gluconeogenesis through activation of Akt. Moreover, in the presence of p38 inhibition SDF-1 could inhibit gluconeogenesis even more strongly. Together, these results suggest that SDF-1 may play a duel role in regulation of hepatic gluconeogenesis. It can inhibit gluconeogenesis by activating Akt while stimulating gluconeogenesis by activation of p38. However, the inhibitory role of SDF-1 is stronger than the stimulatory effect, resulting in a net decrease of gluconeogenesis. Results from this study may provide an investigative opportunity to find new methods for modulating hepatic gluconeogensis, and add a new dimension for chemokine biology. [ABSTRACT FROM AUTHOR]