Rapid glucocorticoid actions in the hypothalamus as a mechanism of homeostatic integration

The hypothalamic paraventricular nucleus (PVN) is a major integrative site for the control of homeostasis, including energy balance, through coordinated regulation of neuroendocrine and autonomic outputs. However, cross-talk regulation of PVN neuroendocrine and preautonomic systems is poorly understood. The stress response invokes the coordinated control of motor, hormonal, and vegetative systems to establish homeostasis after an environmental perturbation. Elevated stress levels of circulating glucocorticoids give rise to multiple, complex physiological effects. The complexity of the glucocorticoid actions is caused by the wide range of glucocorticoid target tissues and to the broad time scale over which the actions occur. Recent studies have revealed rapid glucocorticoid actions in the hypothalamus that may provide an integrative signal linking stress with the regulation of energy and fluid homeostasis. Glucocorticoids inhibit PVN and supraoptic nucleus neurons by stimulating a rapid synthesis and retrograde release of endocannabinoids, which suppress synaptic excitation through presynaptic CB1 receptor activation. The glucocorticoid-induced endocannabinoid synthesis is mediated apparently by a novel membrane-associated glucocorticoid receptor found in multiple subpopulations of hypothalamic neuroendocrine cells. It may, therefore, represent a mechanism for rapid glucocorticoid control of activity among different neuroendocrine systems to coordinate a global response to stress. In support of this, leptin, a circulating adipose signal that regulates food intake and energy expenditure through central actions, blocks the glucocorticoid-mediated endocannabinoid release in the PVN. This represents a means by which the regulation of stress and feeding may interface in the PVN, thus providing a possible mechanism for the integration of multiple homeostatic functions.