Opposing crosstalk between leptin and glucocorticoids rapidly modulates synaptic excitation via endocannabinoid release.
The hypothalamic paraventricular nucleus (PVN) integrates preautonomic and neuroendocrine control of energy homeostasis, fluid balance, and the stress response. We recently demonstrated that glucocorticoids act via a membrane receptor to rapidly cause endocannabinoid-mediated suppression of synaptic excitation in PVN neurosecretory neurons. Leptin, a major signal of nutritional state, suppresses CB(1) cannabinoid receptor-dependent hyperphagia (increased appetite) in fasting animals by reducing hypothalamic levels of endocannabinoids. Here we show that glucocorticoids stimulate endocannabinoid biosynthesis and release via a Galpha(s)-cAMP-protein kinase A-dependent mechanism and that leptin blocks glucocorticoid-induced endocannabinoid biosynthesis and suppression of excitation in the PVN via a phosphodiesterase-3B-mediated reduction in intracellular cAMP levels. We demonstrate this rapid hormonal interaction in both PVN magnocellular and parvocellular neurosecretory cells. Leptin blockade of the glucocorticoid-induced, endocannabinoid-mediated suppression of excitation was absent in leptin receptor-deficient obese Zucker rats. Our findings reveal a novel hormonal crosstalk that rapidly modulates synaptic excitation via endocannabinoid release in the hypothalamus and that provides a nutritional state-sensitive mechanism to integrate the neuroendocrine regulation of energy homeostasis, fluid balance, and the stress response.
Malcher-Lopes
Renato
R
Neuroscience Program, Tulane University, New Orleans, Louisiana 70118, USA. malcherlopes@gmail.com
Di
Shi
S
Marcheselli
Victor S
VS
Weng
Feng-Ju
FJ
Stuart
Christopher T
CT
Bazan
Nicolas G
NG
Tasker
Jeffrey G
JG
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism* / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005938:Glucocorticoids / Q000494:pharmacology / Q000502:physiology*; D005989:Glycerides / Q000378:metabolism; D066298:In Vitro Techniques; D020738:Leptin / Q000502:physiology*; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology*; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D005989:Glycerides; D020738:Leptin; D003907:Dexamethasone; C094503:glyceryl 2-arachidonate; D000242:Cyclic AMP