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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 1 385-393
Copyright © 2003 by The Endocrine Society

Original Article

Modulation of 11ß-Hydroxysteroid Dehydrogenase Type 1 in Mature Human Subcutaneous Adipocytes by Hypothalamic Messengers

Mark Friedberg, Emmanouil Zoumakis, Naoki Hiroi, Tarif Bader, George P. Chrousos and Ze’ev Hochberg

Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Ze’ev Hochberg, M.D., D.Sc., Meyer Children’s Hospital, P.O. Box 9602, Haifa 31096, Israel. E-mail: z_hochberg{at}rambam.health.gov.il.

Glucocorticoids are regulated at the prereceptor level by 11ß-hydroxysteroid dehydrogenase (11ß-HSD), which interconverts inactive cortisone and active cortisol. In a previous study, we noted that patients with hypothalamic obesity had an increased ratio of cortisol/cortisone metabolites, suggesting enhanced 11ß-HSD-1 activity. In this in vitro study, we tested the hypothesis that adipose 11ß-HSD-1 is regulated by the hypothalamus via circulating hormones, sympathetic nervous system innervation, and/or cytokines. Preadipocytes were retrieved from sc fat from healthy nonobese individuals and differentiated in vitro to mature adipocytes. Cells were incubated with several potential effectors, and the activity of 11ß-HSD-1 was assayed by measuring conversion of added 500 nM cortisone to cortisol. Expression of 11ß-HSD-1 mRNA was determined by real-time PCR, whereas lipolytic effects were determined by measuring glycerol concentration in the culture medium. CRH down-regulated 11ß-HSD-1 activity with maximal effect at 10-9M (65 ± 10% of control; P < 0.001) and caused a reduction in lipolysis. Likewise, ACTH down-regulated 11ß-HSD-1 activity with maximal effect at 10-9 M (65 ± 20%; P < 0.05) and reduced medium glycerol. Neither CRH nor ACTH affected 11ß-HSD-1 mRNA expression. TNF{alpha} up-regulated 11ß-HSD-1 activity maximally at 0.6 x 10-9 M (140 ± 20%; P < 0.001); the same cytokine increased 11ß-HSD-1 mRNA levels to 3-fold of control (P < 0.05) and increased medium glycerol levels to 165 ± 14% of control (P < 0.01). IL-1ß also up-regulated 11ß-HSD-1 activity maximally at 0.6 x 10-9 M (160 ± 33%; P < 0.001) and caused an increase in glycerol levels (159 ± 11% of control; P < 0.001). Of the adrenergic agonists, salbutamol up-regulated 11ß-HSD-1 activity maximally at 10-7 M (162 ± 46%; P < 0.02), and clonidine down-regulated it at 10-7 M (82 ± 15%; P < 0.005). We conclude that possible distinct hypothalamic mediators regulating adipose tissue 11ß-HSD-1 might include down-regulation of 11ß-HSD-1 activity by CRH, ACTH, and {alpha}2 sympathetic stimulation, and up-regulation of the enzyme by ß2 sympathetic stimulation and by the cytokines TNF{alpha} and IL-1ß.

Abbreviations: BMI, Body mass index; HPA, hypothalamo-pituitary-adrenal; 11ß-HSD, 11ß-hydroxysteroid dehydrogenase; NADP, nicotinamide adenine dinucleotide phosphate; PRL, prolactin.




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