Opposing crosstalk between leptin and glucocorticoids rapidly modulates synaptic excitation via endocannabinoid release

• Autor(a) principal: Malcher-Lopes, Renato
• Data de Publicação: 2006
• Outros Autores: Shi Di, Marcheselli, Victor S., Feng-Ju, Weng, Stuart, Christopher T., Bazan, Nicolas G., Tasker, Jeffrey G.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UCB
• Texto Completo: http://twingo.ucb.br:8080/jspui/handle/10869/644; https://repositorio.ucb.br:9443/jspui/handle/123456789/7801
• topic: leptin; glucocorticoids; endocannabinoids; neuroendocrine; stress; energy homeostasis

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 CB1 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 G 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.