Activation of Mineralocorticoid Receptors by Exogenous ...

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Abstracts

Translation Highlight from ENDOCRINOLOGY

J Clin Endocrinol Metab, May 2010, 95(5):2513–2518

pancreas, muscle, and white adipose tissue. Insulin and leptin signaling regulate food intake by controlling the expression of orexigenic and anorexigenic neuropeptides in the arcuate nucleus of the hypothalamus via Forkhead box O (Foxo)-1 and signal transducer and activator of transcription-3. Sirt1 has been reported to improve insulin sensitivity in vitro, but the role of hypothalamic Sirt1 in regulating feeding has not been addressed. We found that hypothalamic Sirt1 protein levels increase on feeding, and this induction is abrogated in diet-induced obese mice and db/db mice. We also demonstrate for the first time that Sirt1 protein turnover is regulated by the proteasome and ubiquitination in a hypothalamic cell line and in vivo by feeding, and this regulation is not seen in a pituitary cell line AtT20. Forced expression of wild-type Sirt1 in the mediobasal hypothalamus by adenovirus microinjection suppressed Foxo1-induced hyperphagia, a model for central insulin resistance. Moreover, Sirt1 suppressed Foxo1-dependent expression of the orexigenic neuropeptide Agoutirelated peptide in vitro. We propose that on feeding, Sirt1 protein is stabilized in the hypothalamus, leading to decreased Foxo1-dependent expression of orexigenic neuropeptide Agouti-related peptide and cessation of feeding.

Activation of Mineralocorticoid Receptors by Exogenous Glucocorticoids and the Development of Cardiovascular Inflammatory Responses in Adrenalectomized Rats Morag J. Young, James Morgan, Kim Brolin, Peter J. Fuller, and John W. Funder

(Endocrinology, published April 21, 2010, 10.1210/en.2009-1476) ABSTRACT Activation of the mineralocorticoid receptor (MR) in the context of a high salt intake produces cardiovascular (CV) inflammation plus cardiac fibrosis and failure. Inactivation of vascular 11␤-hydroxysteroid dehydrogenase type 2 activity in intact animals by carbenoxolone (CBX) produces a similar pathology, presumably reflecting coronary vascular MR activation by endogenous glucocorticoids. To test this hypothesis, we have used adrenalectomized rats, without endogenous corticosteroids, and examined the consequences of corticosterone (CORT) replacement on a series of cardiovascular disease parameters. Uninephrectomized adrenalectomized Sprague Dawley rats given 1% NaCl/0.3% KCl to drink were treated for 8 d as follows: control; 20 mg deoxycorticosterone (DOC); 2 mg/d CORT; 2.5 mg/d CBX; CORT plus CBX (CORT/CBX); and CORT/CBX plus 100 mg/kg 䡠 d eplerenone. Markers of cardiac oxidative stress (p22phox and NOX4 mRNA) were up-regulated in the DOC and CORT/CBX groups; in contrast, inflammatory cell infiltration was increased and endothelial nitric oxide synthase down-regulated by CORT as well as by DOC and CORT/CBX. In the kidney, connective tissue growth factor mRNA levels were increased by DOC and CORT/CBX; in contrast, DOC had no effect on mRNA levels for channel inducing factor or endothelin 3, which were elevated only by CORT/CBX. All changes noted were reversed by eplerenone. Rats given 10-fold lower CORT (0.2 mg/d) with or without CBX showed no change in any parameter. These results suggest that there exist distinct but overlapping ligand-specific MR-mediated tissue responses to a classic mineralocorticoid (DOC) and to the glucocorticoid CORT, in the presence and absence of CBX to block vascular 11␤-hydroxysteroid dehydrogenase type 2.

Therapeutic Concentrations of Mitotane (o,pⴕ-DDD) Inhibit Thyrotroph Cell Viability and TSH Expression and Secretion in a Mouse Cell Line Model Maria Chiara Zatelli, Erica Gentilin, Fulvia Daffara, Federico Tagliati, Giuseppe Reimondo, Gianni Carandina, Maria Rosaria Ambrosio, Massimo Terzolo, and Ettore C. degli Uberti

(Endocrinology, published April 14, 2010, 10.1210/en.2009-1404) ABSTRACT Mitotane therapy is associated with many side effects, including thyroid function perturbations mimicking central hypothyroidism, possibly due to laboratory test interference or pituitary direct effects of mitotane. We investigated whether increasing concentrations of mitotane in the therapeutic range might interfere with thyroid hormone assays and evaluated the effects of mitotane on a mouse TSH-producing pituitary cell line. TSH, free T4, and free T3 levels do not significantly change in sera from hypo-, hyper-, or euthyroid patients after addition of mitotane at concentrations in the therapeutic window. In the mouse T␣T1 cell line, mitotane inhibits both TSH expression and secretion, blocks TSH response to TRH, and reduces cell viability, inducing apoptosis at concentrations in the therapeutic window. TRH is not capable of rescuing T␣T1 cells from the inhibitory effects of mitotane on TSH expression and secretion, which appear after short time treatment and persist over time. Our results demonstrate that mitotane does not interfere with thyroid hormone laboratory tests but directly reduces both secretory activity and cell viability on pituitary TSH-secreting mouse cells. These data represent a possible explanation of the biochemical picture consistent with central hypothyroidism in patients undergoing mitotane therapy and open new perspectives on the direct pituitary effects of this drug.

Selective Modulation of Follicle-Stimulating Hormone Signaling Pathways with Enhancing Equine Chorionic Gonadotropin/Antibody Immune Complexes Vanessa Wehbi, Je´re´my Decourtye, Vincent Piketty, Guillaume Durand, Eric Reiter, and Marie-Christine Maurel

(Endocrinology, published March 23, 2010, 10.1210/en.2009-0892) ABSTRACT The injection of equine chorionic gonadotropin (eCG) in dairy goats induces the production of anti-eCG antibodies (Abs) in some females. We have previously shown that Abs negatively modulate the LH and FSH-like bioactivities of eCG, in most cases, compromising fertility in treated females. Surprisingly, we found out that some anti-eCG Abs improved fertility and prolificity of the treated females, in vivo. These Abs, when complexed with eCG, enhanced LH and FSH ability to induce steroidogenesis on specific target cells, in vitro. In the present study, we analyzed the impact of three eCG/anti-eCG Ab-enhancing complexes on two transduction mechanisms triggered by