Glucocorticoids as Counterregulatory Hormones of Leptin: Toward an Understanding of Leptin Resistance

Abstract

The product of the ob gene, leptin, is a hormone secreted by adipose tissue that acts in the hypothalamus to regulate the size of the body fat depot. Its central administration has been shown to decrease food intake and body weight, while favoring energy dissipation. As glucocorticoids are known to play a permissive role in the establishment and maintenance of obesity syndromes in rodents, it was hypothesized that they do so by restraining the effect of leptin. Leptin injected intracerebroventricularly as a bolus of 3 ug in normal rats induced modest reductions in body weight and food intake. In marked contrast, the same dose of leptin had very potent and long-lasting effects in decreasing both body weight and food intake when administered to adrenalectomized rats. Further, glucocorticoid supplementation of adrenalectomized rats dose-dependently inhibited these potent effects of leptin. These data suggest that glucocorticoids play a key inhibitory role in the action of leptin. Under normal conditions, this inhibitory influence of glucocorticoids may prevent lasting hypophagia. In obesity with degrees of hypercorticism, it may contribute to "leptin resistance," whose etiology is still little understood. Diabetes 46:717-719, 1997 P revious experiments have shown that the pathology of rodents with obesity of genetic (1^4), dietary (5), or hypothalamic (6-8) origin can be normalized by adrenalectomy and restored by glucocorticoid replacement (1,7,8). More recently and specifically, it was observed that neuropeptide Y (NPY)-induced obesity-like defects were prevented by adrenalectomy (9). As leptin and NPY have, in normal rats, opposite effects on body weight and food intake (10-19) and as the presence of glucocorticoids favors intracerebroventricular (ICV) NPY-elicited effects (9), it was hypothesized that glucocorticoids could have an inhibitory effect on the action of leptin. This could partly explain why the effect of central or peripheral leptin in decreasing food intake or body weight gain, although definitively present, is relatively weak in amplitude in normal From the Laboratoires de Recherches Metaboliques, Geneva University Medical School, Geneva, Switzerland.Address correspondence and reprint requests to Dr. Katherine E. Zakrzewska, Laboratoires de Recherches Metaboliques, Geneva University Medical School, 64 avenue de la Roseraie, 1211 Geneva 4, Switzerland. E-mail: touabi@cmu.unige.ch.Received for publication 2 December 1996 and accepted in revised form 29 January 1997.ICV, intracerebroventricular; NPY, neuropeptide Y.rodents (11-13). Thus, the purpose of this study was to compare the effects of ICV leptin administration on body weight and food intake in normal and adrenalectomized rats. RESEARCH DESIGN AND METHODSIntact adult sham-operated female Sprague-Dawley rats (body weight, 285 ± 8 g; n = 5) and bilaterally adrenalectomized ones (body weight, 275 ± 5 g; n = 8) purchased from IFFA CREDO (L'Arbresle, France) were used. They were fed ad libitum a standard laboratory diet (Provimi-Lacta, Cossonay, Sw...

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