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Leptin Alters Adrenal Responsiveness by Decreasing Expression of ACTH-R, StAR, and P450c21 in Hypoxemic Fetal Sheep

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Abstract

The late gestation increase in adrenal responsiveness to adrenocorticotropin (ACTH) is dependent upon the upregulation of the ACTH receptor (ACTH-R), steroidogenic acute regulatory protein (StAR), and steroidogenic enzymes in the fetal adrenal. Long-term hypoxia decreases the expression of these and adrenal responsiveness to ACTH in vivo. Leptin, an adipocyte-derived hormone which attenuates the peripartum increase in fetal plasma cortisol is elevated in hypoxic fetuses. Therefore, we hypothesized that increases in plasma leptin will inhibit the expression of the ACTH-R, StAR, and steroidogenic enzymes and attenuate adrenal responsiveness in hypoxic fetuses. Spontaneously hypoxemic fetal sheep (132 days of gestation, PO2 ∼15 mm Hg) were infused with recombinant human leptin (n = 8) or saline (n = 7) for 96 hours. An ACTH challenge was performed at 72 hours of infusion to assess adrenal responsiveness. Plasma cortisol and ACTH were measured daily and adrenals were collected after 96 hours infusion for messenger RNA (mRNA) and protein expression measurement. Plasma cortisol concentrations were lower in leptin- compared with saline-infused fetuses (14.8 ± 3.2 vs 42.3 ± 9.6 ng/mL, P < .05), as was the cortisol:ACTH ratio (0.9 ± 0.074 vs 46 ± 1.49, P < .05). Increases in cortisol concentrations were blunted in the leptin-treated group after ACTH1–24 challenge (F = 12.2, P < .0001). Adrenal ACTH-R, StAR, and P450c21 expression levels were reduced in leptin-treated fetuses (P < .05), whereas the expression of Ob-Ra and Ob-Rb leptin receptor isoforms remained unchanged. Our results indicate that leptin blunts adrenal responsiveness in the late gestation hypoxemic fetus, and this effect appears mediated by decreased adrenal ACTH-R, StAR, and P450c21 expression.

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Authors and Affiliations

  1. Departments of Obstetrics and Gynecology, Wake Forest School of Medicine, 27157, Winston-Salem, NC, USA

    Yixin Su MD, Luke C. Carey PhD, James C. Rose PhD & Victor M. Pulgar PhD

  2. Center for Research in Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Yixin Su MD, Luke C. Carey PhD, James C. Rose PhD & Victor M. Pulgar PhD

  3. Departments of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA

    James C. Rose PhD

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  1. Yixin Su MD
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Correspondence to James C. Rose PhD.

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Su, Y., Carey, L.C., Rose, J.C. et al. Leptin Alters Adrenal Responsiveness by Decreasing Expression of ACTH-R, StAR, and P450c21 in Hypoxemic Fetal Sheep. Reprod. Sci. 19, 1075–1084 (2012). https://doi.org/10.1177/1933719112442246

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