Besides being a fundamental player in eating processes and in hypothalamic regulation of energy balance, the appetite-regulating hormones leptin and ghrelin had been implicated in the etiology of mood disorders. Importantly, particular species of bacteria in the gut are know to affect the levels of leptin and ghrelin. In humans, the onset of depression was associated with a combination of high leptin levels coupled with high visceral fat, and the link between leptin levels and severity of depressive symptoms was mediated by adiposity. It was suggested that leptin might influence depression by acting on leptin receptors present on 5-HT neurons within the raphe nuclei and dopamine neurons in the midbrain and, thus, might influence reward processes. Consistent with this supposition, when leptin receptors in the rat hippocampus were genetically deleted, a stressor-induced depressive profile was apparent, and deletion of leptin receptors on midbrain dopamine neurons in mice elicited elevated anxiety. Thus, identifying the key brain regions that mediate leptin's antidepressant activity and dissecting its intracellular signal transduction pathways may provide new insights into the pathogenesis of depression and facilitate the development of novel therapeutic strategies for the treatment of this illness.