SUMMARY Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (CB1R) is critical for central regulation of food intake. We interrogated whether CB1R-controlled feeding is paralleled by decreased activity of POMC neurons. Chemical promotion of CB1R activity increased feeding, and strikingly, CB1R activation also promoted neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for CB1R-induced feeding, because Designer-Receptors-Exclusively-Activated-by-Designer-Drugs (DREADD)-mediated inhibition of POMC neurons diminished, while DREADD-mediated activation of POMC neurons enhanced CB1R-driven feeding. The Pomc gene encodes both the anorexigenic peptide, α-melanocyte-stimulating hormone (α-MSH), and the peptide, β-endorphin. CB1R activation selectively increased β-endorphin but not α-MSH release in the hypothalamus, and, systemic or hypothalamic administration of the opioid receptor antagonist, naloxone, blocked acute CB1R-induced feeding. These processes involved mitochondrial adaptations, which, when blocked, abolished CB1R-induced cellular responses and feeding. Together, these results unmasked a previously unsuspected role of POMC neurons in promotion of feeding by cannabinoids.

We have shown that synaptic re-organization of hypothalamic feeding circuits in response to metabolic shifts involves astrocytes, cells that can directly respond to the metabolic hormone, leptin, in vitro. It is not known whether the role of glia cells in hypothalamic synaptic adaptions is active or passive. Here we show that leptin receptors are expressed in hypothalamic astrocytes and that conditional, adult deletion of leptin receptors in astrocytes leads to altered glial morphology, decreased glial coverage and elevated synaptic inputs onto pro-opiomelanocortin (POMC)- and Agouti-related protein (AgRP)-producing neurons. Leptin-induced suppression of feeding was diminished, while rebound feeding after fasting or ghrelin administration was elevated in mice with astrocyte-specific leptin receptor deficiency. These data unmask an active role of glial cells in the initiation of hypothalamic synaptic plasticity and neuroendocrine control of feeding by leptin.

40Astrocytes, microglia and tanycytes play active roles in the regulation of hypothalamic feeding circuits. 41These non-neuronal cells are crucial in determining the functional interactions of specific neuronal 42 subpopulations involved in the control of metabolism. Recent advances in biology, optics, genetics and 43 pharmacology resulted in the emergence of novel and highly sophisticated approaches for studying 44 hypothalamic neuronal-glial networks. Here we summarize the progress in the field and argue that 45 glial-neuronal interactions provide a core hub integrating food-related cues, interoceptive signals and 46 internal states to adapt a complex set of physiological responses operating on different time scales to 47 finely tune behavior and metabolism according to metabolic status. This expanding knowledge helps to 48 redefine our understanding of the physiology of food intake and energy metabolism. 50 109AgRP neurons have the ability to rapidly respond to food-related cues rather than to calories per se 21 . 110 Indeed, in vivo calcium imaging of AgRP neurons in freely moving animals has demonstrated their 111 rapidly reductions in activity upon detection of food cues, even before substantial calories are 112 consumed 22,23 . 113 114