Cross talk between leptin and glucocorticoids rapidly controls endocannabinoid release and inhibitory actions in the paraventricular nucleus of the hypothalamus
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Description
The paraventricular nucleus of the hypothalamus (PVN) is the main central integrator in the neuroendocrine and preautonomic control of body homeostasis and the adaptation to stress. Glucocorticoids were shown to stimulate rapid release of an unidentified retrograde messenger in the PVN, which causes inhibition of synaptic glutamate release onto PVN neurosecretory neurons. Fasting leads to increased levels of circulating glucocorticoids and causes increased hypothalamic levels of endocannabinoids. Leptin, a primary signal of nutritional state, blocks endocannabinoid biosynthesis in the hypothalamus and suppresses CB1 cannabinoid receptor-dependent hyperphagia in fasting animals. Whole-cell-patch-clamp recordings and biochemical assays followed by liquid chromatography-mass spectrometry analysis were used in acute hypothalamic slices to test two main hypothesis: (1) that glucocorticoids rapidly stimulates the biosynthesis and release of endocannabinoids in the PVN, causing inhibition of synaptic glutamate release onto PVN neurons; and (2) that leptin blocks glucocorticoid-induced synthesis of endocannabinoids in the PVN, preventing glucocorticoid inhibitory effect. The data presented here support both hypothesis and further demonstrate that (1) glucocorticoids rapidly trigger the biosynthesis and retrograde release of the endocannabinoids anandamide and 2-arachdonylglycerol in the PVN by a mechanism that depends on the activation of a membrane receptor and a Galpha s-cAMP-PKA signaling pathway; (2) leptin blocks glucocorticoid-induced endocannabinoid biosynthesis in the PVN by triggering ob-R leptin receptor-dependent activation of phosphodiesterase 3B; and (3) leptin blocks glucocorticoid-induced, CB1 cannabinoid receptor-dependent inhibition of glutamatergic inputs to oxytocin- and vasopressin-expressing PVN magnocellular neurons, which are involved in energy homeostasis, fluid balance, hemodynamics and the stress response in male rats. This hormonal interaction is likely to mediate PVN-dependent preautonomic and neurosecretory adaptations that take place to maintain energy homeostasis during basal and stress-related conditions, including caloric deficit during fasting and satiety upon refeeding. Furthermore, the non-genomic interaction between glucocorticoids- and leptin-activated signaling pathways demonstrated here reveals a nutritional state-sensitive, endocannabinoid-mediated regulatory mechanism to modulate and coordinate the hypothalamic control of energy homeostasis, fluid balance and the stress response. Sustained elevated circulating levels of GCs (e.g., by chronic stress or depression) or leptin (e.g., by obesity) could result in deregulation of this mechanism, leading to eating, metabolic and cardiovascular disorders