Leptin is probably the most studied adipose-derived hormones. Leptin which is mainly produced by adipocytes exerts its effects both peripherally and centrally [
17,
21,
24,
64]. This adipokine plays a key role in regulating energy intake and expenditure, metabolism, and behavior by directly acting on the CNS. Mice invalidated for leptin (ob/ob mice) display obesity, insulin resistance, and hyperphagia showing notably the impact of this adipose-derived hormone on feeding behavior [
65]. Peripheral leptin exerts its central effect through its binding at the level of choroid plexus leading to its transport across the blood brain barrier [
66‐
69]. Such a transport involved leptin receptors and probably other mechanisms that are still poorly understood [
9]. However, some studies have shown that leptin could be also locally and
de novo produced in the brain, in the cerebellum, the cortex, and the hypothalamus [
70‐
73], suggesting other specific and local functions for leptin than those previously described. Leptin receptors belong to the family of cytokine receptors, and at least five different isoforms have been identified in mouse: Ob-Ra to Ob-Re [
65,
74]. In the CNS, leptin receptors (Ob-R or LepR) were first identified in choroid plexus and in the hypothalamus [
75,
76]. Among all Ob-R isoforms, only the full-length isoform (Ob-Rb) appears to fully transduce the activation signal at least in the brain and is essential for leptin’s weight-reducing effects [
65,
74]. Ob-Rb is expressed in the hypothalamic nuclei notably in the arcuate nucleus (ARC), the dorsomedial nucleus (DMH), the paraventricular nucleus (PVN), the ventromedial hypothalamic nucleus (VMH), and the lateral hypothalamic nucleus (LH) [
65,
77,
78] but is also detected in the neocortex, the hippocampus, the hindbrain (nucleus of the solitary tract), the ventral tegmental area, the medulla, and the cerebellum [
77,
79‐
83]. In addition, a weaker expression was also detected by
in situ hybridization in the hippocampus and the thalamus [
77]. The expression of leptin receptors and leptin mRNAs is documented in the mouse brain and notably in the main neurogenic niches, the subventricular zone of the lateral ventricles, and the dentate gyrus of the hippocampus (Allen Brain Atlas [
http://www.brain-map.org], [
84]). This work clearly illustrates the expression of leptin receptors in the cortex, along the ventricular walls and also in the hippocampus. Leptin is expressed in the same regions at lower levels. In the hypothalamus, the primary leptin targets are the orexigenic agouti-related peptide (AgRP) neurons and the anorexigenic pro-opiomelanocortin (POMC) neurons that are involved in feeding behavior. Thus, in the CNS, leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus [
85]. The appetite-stimulating effects of AgRP/NPY are inhibited by leptin in the arcuate nucleus avoiding the release of orexigenic factors [
86,
87]. Furthermore, leptin receptors were also expressed in glutamatergic and GABAergic neurons [
78,
88,
89]. Vong and colleagues (2011) have shown that the main effects of leptin are mediated by GABAergic neurons and only barely by glutamatergic neurons [
88]. However, it was recently demonstrated that glutamate release mediates leptin action on energy expenditure [
89]. We realize now that the effects of leptin on these different neuronal types and brain nuclei are not so easy to understand as originally thought. In homeostatic conditions, leptin inhibits food intake, and in extra-hypothalamic sites, leptin acts on neurogenesis, synaptogenesis, neuronal excitability, and neuroprotection [
9,
90,
91]. Leptin was also shown to improve cognition and mood in depressed and anxious animal models, notably by improving long-term potentiation [
9]. Leptin levels negatively correlated with the development of Alzheimer’s disease in lean humans [
91,
92], and leptin signaling seems to be dysregulated in Alzheimer’s disease brains [
93]. Interestingly, there are also positive correlations between plasma levels of leptin and body weight [
94,
95].