Increased ATP content/production in the hypothalamus may be a signal for energy-sensing of satiety: studies of the anorectic mechanism of a plant steroidal glycoside

A steroidal glycoside with anorectic activity in animals, termed P57AS3 (P57), was isolated from Hoodia gordonii and found to have homologies to the steroidal core of cardiac glycosides. Intracerebroventricular (i.c.v.) injections of the purified P57AS3 demonstrated that the compound has a likely central (CNS) mechanism of action. There is no evidence of P57AS3 binding to or altering activity of known receptors or proteins, including Na/K-ATPase, the putative target of cardiac glycosides. The studies demonstrated that the compound increases the content of ATP by 50-150% in hypothalamic neurons. In addition, third ventricle (i.c.v.) administration of P57, which reduces subsequent 24-h food intake by 40-60%, also increases ATP content in hypothalamic slice punches removed at 24 It following the i.c.v. injections. In related studies, in pair fed rats fed a low calorie diet for 4 days, the content of ATP in the hypothalami of control i.c.v. injected animals fell by 30-50%, which was blocked by i.c.v. injections of P57AS3. With growing evidence of metabolic or nutrient-sensing by the hypothalamus, ATP may be a common currency of energy sensing, which in turn may trigger the appropriate neural, endocrine and appetitive responses as similar to other fundamental hypothalamic homeostatic centers for temperature and osmolarity. (C) 2004 Elsevier B.V. All rights reserved.