Journal Article

Hypothalamic POMC neurons promote cannabinoid-induced feeding

Kim, Jung Dae, Vianna, Claudia R., Cowley, Michael A., Elmquist, Joel K., Bechmann, Ingo, Gao, Xiao-Bing, Dietrich, Marcelo O., Szigeti-Buck, Klara, Koch, Marco, Castorena, Carlos M., Simonds, Stephanie E., Diano, Sabrina, Kim, Jae Geun, Morozov, Yury M., Rakic, Pasko, Horvath, Tamas L., Hernández-Nuño, Francisco, Varela, Luis

2015

Overview

Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (CB 1 R) is critical for the central regulation of food intake. Here we test whether CB 1 R-controlled feeding in sated mice is paralleled by decreased activity of POMC neurons. We show that chemical promotion of CB 1 R activity increases feeding, and notably, CB 1 R activation also promotes neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for CB 1 R-induced feeding, because designer-receptors-exclusively-activated-by-designer-drugs (DREADD)-mediated inhibition of POMC neurons diminishes, whereas DREADD-mediated activation of POMC neurons enhances CB 1 R-driven feeding. The Pomc gene encodes both the anorexigenic peptide α-melanocyte-stimulating hormone, and the opioid peptide β-endorphin. CB 1 R activation selectively increases β-endorphin but not α-melanocyte-stimulating hormone release in the hypothalamus, and systemic or hypothalamic administration of the opioid receptor antagonist naloxone blocks acute CB 1 R-induced feeding. These processes involve mitochondrial adaptations that, when blocked, abolish CB 1 R-induced cellular responses and feeding. Together, these results uncover a previously unsuspected role of POMC neurons in the promotion of feeding by cannabinoids. Cannabinoid-induced feeding signals are shown to enhance pro-opiomelanocortin (POMC) neuronal activity in mice, causing an enhancement of β-endorphin release, which is crucial in causing this cannabinoid-induced response; these results uncover an overlooked role of hypothalamic POMC neurons in the promotion of feeding by cannabinoids. Complex effects of cannabinoids on feeding Previous work has established a role for hypothalamic pro-opiomelanocortin (POMC) neurones in reducing feeding due to satiety, suggesting that signals promoting feeding may reduce POMC neuronal activity. Tamas Horvath and colleagues have tested this idea and find that, surprisingly, cannabinoid feeding signals enhance POMC neuronal activity. This paradoxical POMC neuronal activation is indispensable for appropriate promotion of feeding triggered by cannabinoid receptor 1 activation in the state of satiety. The authors conclude that the overall effect of cannabinoids on feeding may be driven by both pre- and post-synaptic effects — possibly independently from one another — and that it is their temporal synchrony that brings about the overall behavioural changes.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/51 / 14/28 / 631/378/1488/1562 / 64/60 / 82 / 82/80 / 9/74 / alpha-MSH - metabolism / Analysis / Animal feeding behavior / Animals / beta-Endorphin - metabolism / Cannabinoids / Cannabinoids - pharmacology / Eating - drug effects / Eating - physiology / Energy Metabolism - drug effects / Feeding / Health aspects / Humanities and Social Sciences / Hunger / Hypothalamus - cytology / Hypothalamus - drug effects / Hypothalamus - physiology / Ion Channels - metabolism / Male / Marijuana / Mice / Mice, Inbred C57BL / Mitochondria - drug effects / Mitochondria - metabolism / Mitochondrial Proteins - metabolism / multidisciplinary / Naloxone - pharmacology / Neurons / Neurons - drug effects / Neurons - metabolism / Peptides / Pro-opiomelanocortin / Pro-Opiomelanocortin - metabolism / Proteins / Receptor, Cannabinoid, CB1 - agonists / Receptor, Cannabinoid, CB1 - metabolism / Rodents / Satiety Response - drug effects / Satiety Response - physiology / Science / Uncoupling Protein 2