Leptin induces insulin-like signaling that antagonizes cAMP elevation by glucagon in hepatocytes

Although many effects of leptin are mediated through the central nervous sy stem, leptin can regulate metabolism through a direct action on peripheral tissues, such as fat and liver. We show here that leptin, at physiological concentrations, acts through an intracellular signaling pathway similar to that activated by insulin in isolated primary rat hepatocytes, This pathway involves stimulation of phosphatidylinositol 3-kinase (PI3K) binding to in sulin receptor substrate-1 and insulin receptor substrate-a, activation of PI3K and protein kinase B (AKT), and PI3K-dependent activation of cyclic nu cleotide phosphodiesterase 3B, a cAMP-degrading enzyme. One important funct ion of this signaling pathway is to reduce levels of cAMP, because leptin-m ediated activation of both protein kinase B and phosphodiesterase 3B is mos t marked following elevation of cAMP by glucagon, and because leptin suppre sses glucagon-induced cAMP elevation in a PI3K-dependent manner. There is l ittle or no expression of the long form leptin receptor in primary rat hepa tocytes, and these signaling events are probably mediated through the short forms of the leptin receptor. Thus, leptin, like insulin, induces an intra cellular signaling pathway in hepatocytes that culminates in cAMP degradati on and an antagonism of the actions of glucagon.