Adrenalectomy Alters the Sensitivity of the Central Nervous System Melanocortin System

Abstract

Removal of adrenal steroids by adrenalectomy (ADX) reduces food intake and body weight in rodents and prevents excessive weight gain in many genetic and dietary models of obesity. Thus, glucocorticoids appear to play a key role to promote positive energy balance in normal and pathological conditions. By comparison, central nervous system melanocortin signaling provides critical inhibitory tone to regulate energy balance. The present experiments sought to test whether glucocorticoids influence energy balance by altering the sensitivity to melanocortin receptor ligands. Because melanocortin-producing neurons are hypothesized to be downstream of leptin in a key weight-reducing circuit, we tested rats for their sensitivity to leptin and confirmed reports that the hypophagic response to third ventricular (i3vt) leptin is increased in ADX rats and is normalized by glucocorticoid replacement. Next we tested rats for their sensitivity to the melanocortin agonist melanotan II and found that, as for leptin, ADX enhanced the hypophagic response via a glucocorticoiddependent mechanism. The central nervous system melanocortin system is unique in that it includes the endogenous melanocortin receptor antagonist, AgRP. The orexigenic effect of i3vt AgRP was absent in ADX rats and restored by glucocorticoid replacement. We conclude that the potent weight-reducing effects of ADX likely involve heightened responsiveness to melanocortin receptor stimulation. Diabetes 52

Neonatal capsaicin causes compensatory adjustments to energy homeostasis in rats

“…On the other hand, a lower level of circulating glucocorticoids might have contributed to the increased leptin signaling by hypothalamic neuronal networks [39] in CAP-treated rats. In fact, a reduction in glucocorticoid levels could underlie the "healthier" endocrine and metabolic profile of the CAP rats in the present study, since removal of adrenals resulting in other studies has been shown to increase insulin sensitivity and metabolism and reduce body weight gain even in rats which have a deficient leptin signaling system [40][41][42].…”

Pro-opiomelanocortin (POMC)-derived peptides and the regulation of energy homeostasis

“…For example, adrenalectomy is able to reverse the obese phenotype and restore hypothalamic melanocortin tone in leptin-deficient ob/ob mice (12). In addition, adrenalectomy alters the sensitivity of the central melanocortin system to the effects of the melanocortin antagonist AgRP, with the orexigenic effect of this peptide being absent in adrenalectomised rats but restored with GC supplementation (13).…”

In Vivo Evidence for Inverse Agonism of Agouti-Related Peptide in the Central Nervous System of Proopiomelanocortin-Deficient Mice

“…Because responses to melanocortin antagonists apparently require the presence of circulating glucocorticoids (26), we compared Pomc Ϫ/Ϫ mice with a global deficiency of POMC and adrenal insufficiency to Pomc Ϫ/Ϫ Tg/ϩ mice with a neural-specific deficiency of POMC but restored glucocorticoids (4). Feeding effects of the orexigenic gut peptide ghrelin (27) were also tested.…”