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.
Division of Endocrinology, Hallett Center for Diabetes and Endocrinology, Brown
Medical School, Coro Building Providence, RI 02903, USA. david_b_maclean@brown.edu
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 h 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.