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Cryptochrome 2 Expression Level Is Critical for Adrenocorticotropin Stimulation of Cortisol Production in the Capuchin Monkey Adrenal

Programa de Fisiopatología (C.T.-F., L.A.-C., F.J.V., N.M., M.S.-F.), Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 6640871, Chile; Facultad de Ciencias Biológicas (C.T.-F.), Pontificia Universidad Católica de Chile Casilla 114D, Santiago, Chile; Instituto de Anatomía, Histología, y Patología (H.G.R.), Facultad de Medicina, Universidad Austral de Chile Casilla 167, Valdivia, Chile; Department of Women’s Health (G.J.V.), Arrowhead Regional Medical Center, Colton, California 92324; and Universidad de Tarapaca (M.S.-F.), CP 1000007 Arica, Chile

Address all correspondence and requests for reprints to: Dr. María Serón-Ferré, Ph.D., Departamento de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Casilla 16038, Santiago 9, Santiago, Chile. E-mail: mseron{at}med.uchile.cl.

Timely production of glucocorticoid hormones in response to ACTH is essential for survival by coordinating energy intake and expenditure and acting as homeostatic regulators against stress. Adrenal cortisol response to ACTH is clock time dependent, suggesting that an intrinsic circadian oscillator in the adrenal cortex contributes to modulate the response to ACTH. Circadian clock gene expression has been reported in the adrenal cortex of several species. However, there are no reports accounting for potential involvement of adrenal clock proteins on cortisol response to ACTH. Here we explored whether the clock protein cryptochrome 2 (CRY2) knockdown modifies the adrenal response to ACTH in a primate. Adrenal gland explants from adult capuchin monkey (n = 5) were preincubated for 6 h with transfection vehicle (control) or with two different Cry2 antisense and sense probes followed by 48 h incubation in medium alone (no ACTH) or with 100 nM ACTH. Under control and sense conditions, ACTH increased cortisol production, whereas CRY2 suppression inhibited ACTH-stimulated cortisol production. Expression of the steroidogenic enzymes steroidogenic acute regulatory protein and 3β-hydroxysteroid dehydrogenase at 48 h of incubation was increased by ACTH in control explants and suppressed by Cry2 knockdown. Additionally, we found that Cry2 knockdown decreased the expression of the clock gene brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein (Bmal1) at the mRNA and protein levels. Altogether these results strongly support that the clock protein CRY2 is involved in the mechanism by which ACTH increases the expression of steroidogenic acute regulatory protein and 3β-hydroxysteroid dehydrogenase. Thus, adequate expression levels of components of the adrenal circadian clock are required for an appropriate cortisol response to ACTH.

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				C. W. Wilkinson Adrenocortical Responsiveness to Adrenocorticotropin: StAR Is Ascendant Endocrinology, June 1, 2009; 150(6): 2509 - 2511. [Full Text] [PDF]