Fig. 2.

Interactions of leptin and ghrelin with the endocannabinoid system (ECS) in hypothalamic neurons. Peripheral-derived hormones such as leptin and ghrelin stimulate specific areas of the hypothalamus that coordinate the energy balance. The ECS is emerging as an important integrator in these signaling pathway. (a) Leptin acts in parvocellular neuroendocrine cells of the paraventricular nucleus of the hypothalamus (PVN) by reducing the endocannabinoid (eCB) synthesis and release through the membranous glucocorticoid receptor (mbGR) blockade. This effect increases glutamate release from glutamatergic synapsis to the PVN neurons. (b) In addition to leptin, ghrelin acts on parvocellular neurons of the PVN. The bind of ghrelin to its receptor triggers an intracellular Ca²⁺ level increase leading to 2-AG synthesis. The release of 2-AG into the extracellular space, activates the presynaptic CB1 inhibiting the release of glutamate from the axons innervating PVN neurons. (c) In lateral hypothalamus (LH), the activation of leptin receptor (LepR) in prefornical LH neurons results in less synthesis and release of eCB. This effect led to an increase in the GABAergic inhibitory tone to melanocortin-concentrating hormone (MCH) neurons to control food intake and appetite. (d) Leptin also acts on SF-1 neurons of the ventromedial nucleus of the hypothalamus (VMH). Although molecular mechanisms are not fully described, CB-1 dependent endocannabinoid signaling interferes in the leptin activation of SF-1 neurons. (e) Within the arcuate nucleus (ARC), on the one hand leptin activates POMC neurons and reduces eCB synthesis and release. On the other hand, CB1 agonists increase the secretion of NPY in AgRP/NPY neurons