Unexpected amplification of leptin-induced Stat3 signaling by urocortin: implications for obesity.

Cooperativity among ingestive peptides reflects attempts by the body to finely control its weight. Urocortin, like leptin, is a potent suppressor of food intake, and they interact at the blood-brain barrier (BBB). After injection into the hypothalamus, urocortin can stimulate the release of leptin in the periphery. It is not known, however, whether urocortin, known to signal through adenylate cyclase and elevate cAMP, can potentiate signal transducer and activator of transcription (Stat) 1 and 3 signaling known to mediate the actions of leptin. We examined the interactions between urocortin and leptin signaling in two cellular systems: HEK293 cells and cerebral microvessel endothelial RBE4 cells, a model of the BBB. Both cell lines have low basal levels of CRHR1 and CRHR2 (receptors for urocortin) and ObRs (receptors for leptin). The cells were cotransfected with the receptors and luciferase reporters to determine the level of Stat1 or Stat3 activation 6 h after treatment with leptin, urocortin, or both. Urocortin induced significant Stat3 but not Stat1 activation, mediated by either CRHR1 or CRHR2. Leptin signaling by ObRb caused a large increase of both Stat1 and Stat3, and this was significantly potentiated by the addition of urocortin, being more robust for Stat3 than Stat1. The interactions of leptin and urocortin were not reciprocal, as leptin failed to further increase urocortin-mediated cAMP production. By unexpectedly potentiating leptin signaling through Stat, urocortin amplifies the cellular response of leptin. This novel phenomenon suggests that urocortin can play an important compensatory role during leptin resistance in obesity.