Leptin is an adipocyte-derived hormone that regulates body fat stores and feeding behavior. In an effort to identify endogenous diffusible modulators of leptin production, we found that endothelin-1 (ET-1) up-regulates leptin expression in adipocytes. ET-1 is as potent and efficacious as insulin in stimulating leptin production in two different adipocyte cell lines. Endothelins stimulate leptin production via the endothelin-A receptor (ET A), as judged by a potency rank order of ET-1 ≫ ET-3. We detected expression of ETA but not ETB in both cell lines by Northern blot analysis. In addition, the ETA-selective antagonist FR139317 inhibited ET-1-induced leptin expression more potently than did the ETB-selective antagonist BQ788. ET-1 and insulin positively interact with each other in increasing leptin production in adipocytes. In primary mouse white fat cells, we detected expression of both ETA and ET B by Northern blot and in situ hybridization analyses. We conclude that ET-1 stimulates leptin production via the ETA receptor in cultured adipocytes.
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