Leptin Interferes with Adrenocorticotropin/3′,5′-Cyclic Adenosine Monophosphate (cAMP) Signaling, Possibly through a Janus Kinase 2-Phosphatidylinositol 3-Kinase/Akt-Phosphodiesterase 3-cAMP Pathway, to Down-Regulate Cholesterol Side-Chain Cleavage Cytochrome P450 Enzyme in Human Adrenocortical NCI-H295 Cell Line
| العنوان: | Leptin Interferes with Adrenocorticotropin/3′,5′-Cyclic Adenosine Monophosphate (cAMP) Signaling, Possibly through a Janus Kinase 2-Phosphatidylinositol 3-Kinase/Akt-Phosphodiesterase 3-cAMP Pathway, to Down-Regulate Cholesterol Side-Chain Cleavage Cytochrome P450 Enzyme in Human Adrenocortical NCI-H295 Cell Line |
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| المؤلفون: | Yi-Ning Chiu, King-Jen Chang, Yuan-Ching Chang, Hao-Ting Hsu, Chien-Liang Liu, Ing-Cherng Guo |
| المصدر: | The Journal of Clinical Endocrinology & Metabolism. 91:2761-2769 |
| بيانات النشر: | The Endocrine Society, 2006. |
| سنة النشر: | 2006 |
| مصطلحات موضوعية: | Leptin, Cholera Toxin, endocrine system, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Phosphodiesterase 3, Gene Expression, Adrenocorticotropic hormone, Biochemistry, Phosphatidylinositol 3-Kinases, chemistry.chemical_compound, Endocrinology, Adrenocorticotropic Hormone, Cell Line, Tumor, Proto-Oncogene Proteins, Internal medicine, Cyclic AMP, medicine, Humans, Cyclic adenosine monophosphate, Cholesterol Side-Chain Cleavage Enzyme, RNA, Messenger, Phosphorylation, Promoter Regions, Genetic, Protein kinase B, Leptin receptor, Janus kinase 2, biology, Phosphoric Diester Hydrolases, Cholesterol side-chain cleavage enzyme, Biochemistry (medical), Janus Kinase 2, Protein-Tyrosine Kinases, Adrenal Cortex Neoplasms, chemistry, Adrenal Cortex, biology.protein, Steroids, Janus kinase, Proto-Oncogene Proteins c-akt, hormones, hormone substitutes, and hormone antagonists, Signal Transduction |
| الوصف: | Obesity has adverse effects on adrenocortical functions. Adipocyte-derived leptin, a biomarker molecule of obesity, may directly control adrenal steroidogenesis via an unclear mechanism.We studied the mechanism underlying leptin action on adrenal steroidogenesis in human adrenocortical NCI-H295 tumor cell line.Levels of progesterone, cortisol, and cAMP were determined by ELISA. Western blotting was used to detect protein amounts of P450 side-chain cleavage (P450scc), Janus kinase 2 (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.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 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 phosphatidylinositol 3-kinase/Akt (wortmannin) as well as inhibitors of cAMP-degrading phosphodiesterases (PDEs), including nonspecific 3-isobutyl-1-methylxanthine and PDE3-specific SKF94836. Leptin failed to affect the inductions of CYP11A1 promoter activity and steroid secretion by PDE-nonhydrolyzable N(6)-monobutyryl-cAMP.Leptin interferes with ACTH/cAMP signaling, possibly through a cAMP-degrading mechanism involving activation of JAK2, phosphatidylinositol 3-kinase, and PDE3, to down-regulate P450scc expression and consequent adrenal steroidogenesis. |
| تدمد: | 1945-7197 0021-972X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d0aee40cd84f993f7f1bff20e2e30991 https://doi.org/10.1210/jc.2005-2383 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....d0aee40cd84f993f7f1bff20e2e30991 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19457197 0021972X |
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