LEPTIN RECEPTOR ACTION IN HEPATIC CELLS

Leptin, an adipocyte-secreted hormone, is one of the central regulator s of body weight homeostasis. In humans and rodents, two major forms o f leptin receptors (OB-R) are expressed. The short form (OB-R-S), cons idered to lack signaling capability, is detected in many organs. In co ntrast, OB-R long form (OB-R-L) predominates in the hypothalamus, but is also present at low levels in peripheral tissues. Transient transfe ction experiments have demonstrated that OB-R-L transduces an intracel lular signaling similar to interleukin (IL)-6 type-cytokine receptors. To define the specificity by which OB-R induces genes and cooperates with signal transduction pathways utilized by other hormones and cytok ines, rat and human hepatoma cell lines were generated which stably ex press human OB-R-L. Hepatoma cell lines selected for appreciable level s of OB-R-L mRNA display enhanced leptin binding and responded to lept in with an IL-6 receptor-like signaling that includes the activation o f STAT proteins, induction of acute-phase plasma proteins, and synergi sm with IL-1 and tumor necrosis factor-alpha. A leptin-mediated recrui tment of phosphatidylinositol 3-kinase to insulin receptor substrate-2 was also detected. However, no significant tyrosine phosphorylation o f insulin receptor substrate-2 and modulation of the immediate cell re sponse to insulin were observed. The data suggest that OB-R-L action i n hepatic cells is equivalent to that of IL-6 receptor. However, lepti n does not play a specific role in muting insulin action on hepatoma c ells and therefore may not contribute to the diabetic symptoms associa ted with obesity.