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Submitted on November 1, 2005
Accepted on April 28, 2006
Department of Veterinary Medicine, College of Bio-Resources and Agriculture, National Taiwan University, Taipei, Taiwan; Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Medicine, Nursing and Management College, Taipei, Taiwan; Department of Surgery, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
* To whom correspondence should be addressed. E-mail: iguo{at}ntu.edu.tw.
Context: Obesity has adverse effects on adrenocortical functions. Adipocyte-derived leptin, a biomarker molecule of obesity, may directly control adrenal steroidogenesis via an unclear mechanism.
Objective: We studied the mechanism underlying leptin action on adrenal steroidogenesis in human adrenocortical NCI-H295 tumor cell line.
Methods: Levels of progesterone, cortisol and cAMP were determined by ELISA. Western blotting was used to detect protein amounts of P450scc, JAK2, Akt and their phosphorylated forms. The mRNA expressions of P450scc and leptin receptors were measured by RT-PCR and real-time PCR. P450scc promoter activity was analyzed with a luciferase reporter system.
Results: Cholera toxin mimicked ACTH action by increasing adrenal cAMP levels and steroid secretion. Leptin did not affect basal release but significantly inhibited ACTH/cholera toxin-induced steroid secretion. The concomitant inhibitions by leptin on cholera toxin-induced protein and ACTH/cholera toxin-induced mRNA expression of P450scc were confirmed. Leptin inhibited ACTH/cholera toxin-induced CYP11A1 promoter activity via a known cAMP-responsive region located between -1.7 kb and -1.5 kb. Leptin activated phosphorylations of JAK2 and Akt. Inhibitory effects of leptin on ACTH/cholera toxin-induced cAMP levels, CYP11A1 promoter activity and steroid secretion were blunted by either inhibitor of JAK2 (AG490) or PI3K/Akt (Wortmannin), as well as inhibitors of cAMP-degrading phosphodiesterases (PDEs), including non-specific IBMX and PDE3-specific SKF94836. Leptin failed to affect the inductions of CYP11A1 promoter activity and steroid secretion by PDE-non-hydrolyzable N6-MB-cAMP.
Conclusions: Leptin interferes with ACTH/cAMP signaling possibly through a cAMP-degrading mechanism involving activation of JAK2, PI3K and PDE3 to down-regulate P450scc expression and consequent adrenal steroidogenesis.
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