Vol. 8, No. 1 85 Leptin Regulation by Corticosteroids and Insulin/Tan et al. Received August 18, 1997; Revised October 31, 1997; Accepted November 17, 1997. Author to whom all correspondence and reprint requests should be addressed: Dr. Shing C. Hooi, Department of Physiology, Faculty of Medicine, National University of Singapore, 10, Kent Ridge Crescent, Singapore 119260. E-mail: phshsc@nus.edu.sg Endocrine, vol. 8, no. 1, 85–92, February 1998 0969–711X/98/8:85–92/$10.00 © 1998 by Humana Press Inc. All rights of any nature whatsoever reserved. 85 Leptin is an important hormone that has potent effects on appetite and body weight. The regulation of leptin gene expression and secretion by corticosteroids and insulin was studied in the rat. Adrenalectomy resulted in a significant reduction in leptin gene expression and secretion. The reduction was corrected by hormonal replacement with corticosterone pellets, showing that normal levels of circulating corticosteroids are required to maintain leptin expression and secretion in the body. Chronic treatment with dexamethasone (DEX) over 3 wk did not significantly increase leptin gene expression and secretion, contrary to earlier reports using shorter treatment paradigms. The profound weight loss associated with chronic DEX treatment may have abrogated the direct stimulatory effect of DEX on leptin gene expression and secretion, indicat- ing a possible crosstalk between corticosteroids and leptin in the regulation of body weight. Shorter-term treatment of animals with DEX (3.7 μg/g body wt; 24 h) increased leptin gene expression and secretion about 2-fold and 1.4-fold, respectively. The increase was independent of circulating insulin concentrations. In streptozotocin-treated rats, short-term DEX treat- ment increased leptin gene expression and secretion about 3.5-fold and 2-fold, respectively. The data indicate that circulating leptin concentrations and adipose tissue leptin expression are dependent on corticosteroids and insulin. Although acute DEX treat- ment resulted in a stimulatory effect on leptin secre- tion and expression, chronic DEX treatment did not. The stimulatory effect of DEX on leptin is independent of circulating insulin concentrations Key Words: Leptin; corticosteroids; adrenalectomy; insulin; body weight. Introduction Energy balance is tightly regulated in the body by a variety of different hormones, including glucocorticoids and insulin (1). Recently, the mouse obese (ob) gene and its human homolog was identified and cloned using positional cloning techniques (2). The ob gene is specifically expressed in adipocytes and encodes a 167 amino acid secreted pep- tide called leptin (2–6). It has been postulated that leptin acts as a feedback signal to regulate energy stores in the body (7,8). In support of this hypothesis, plasma leptin con- centrations and mRNA levels in adipose tissue change in parallel with body weights and fat stores (4,9,10). Leptin is thought to act on the hypothalamus to effect changes in appetite and metabolism to control energy balance (7,8,11). The potent effects of leptin on energy balance in the body has prompted studies on the regulation of leptin gene expression and secretion. Both corticosteroids (5,12–14) and insulin (15–17) have been shown to have effects on leptin gene expression and secretion. Recently, De Vos et al. (12) showed that catabolic doses of glucocorticoids resulted in a decrease in body weight gain and food intake, which were correlated to an increase in leptin mRNA expression in epididymal fat. The glucocorticoid-induced decrease in body weight gain and food intake was thought to be mediated by changes in leptin gene expression. Although short-term treatment with glucocorticoids has the ability to enhance leptin expression and secretion, the longer term physiological effects have not yet been fully characterized. In this present work, we studied the effects of adrenalectomy and corticosterone replacement, as well as dexamethasone (DEX) treatment on leptin mRNA and plasma leptin concentrations. Since glucocorticoids are known to increase plasma insulin levels (1), we also studied the involvement of insulin in mediating the stimulatory effect of DEX on leptin gene expression and secretion in the body. Regulation of Leptin Expression and Secretion by Corticosteroids and Insulin Implications for Body Weight Jacqueline T. T. Tan, 1 Bharati K. Patel, 1 Lee M. Kaplan, 2 James I. Koenig, 3 and Shing C. Hooi 1 1 Department of Physiology, Faculty of Medicine, National University of Singapore, 10 Kent Ridge Crescent, Singapore; 2 Gastrointestinal Unit, Jackson 802, Massachusetts General Hospital, Boston, MA; and 3 Maryland Psychiatric Research Center, University of Maryland School of Medicine, P.O. Box 21247, Baltimore, MD