Ghrelin is a hormone that stimulates growth hormone secretion and signals energy insufficiency via interaction with its receptor, the growth hormone secretagogue receptor (GHSR). The GHSR is located in both the central nervous system and the periphery. Its distribution in the CNS, as assessed by in situ hybridization histochemistry (ISHH), has been described previously in a few mammalian species, although these studies were limited by either the detail provided or the extent of the regions examined. In the present study, we systematically examined the distribution of GHSR mRNA in the adult rat and mouse brains and cervical spinal cords by using ISHH with novel cRNA probes specific for the mRNA encoding functional GHSR (the type 1a variant). We confirmed GHSR mRNA expression in several hypothalamic nuclei, many of which have long been recognized as playing roles in body weight and food intake. GHSR also was found in several other regions previously unknown to express GHSR mRNA, including many parasympathetic preganglionic neurons. Additionally, we found GHSR mRNA within all three components of the dorsal vagal complex, including the area postrema, the nucleus of the solitary tract, and the dorsal motor nucleus of the vagus. Finally, we examined the co-expression of GHSR with tyrosine hydroxylase and cholecystokinin, and demonstrate a high degree of GHSR mRNA expression within dopaminergic, cholecystokinin-containing neurons of the substantia nigra and ventral tegmental area.

Leptin, an adipocyte-derived hormone, acts directly on the brain to control food intake and energy expenditure. An important question is the identity of first-order neurons initiating leptin's anti-obesity effects. A widely held view is that most, if not all, of leptin's effects are mediated by neurons located in the arcuate nucleus of the hypothalamus. However, leptin receptors (LEPRs) are expressed in other sites as well, including the ventromedial hypothalamus (VMH). The possible role of leptin acting in "nonarcuate" sites has largely been ignored. In the present study, we show that leptin depolarizes and increases the firing rate of steroidogenic factor-1 (SF1)-positive neurons in the VMH. We also show, by generating mice that lack LEPRs on SF1-positive neurons, that leptin action at this site plays an important role in reducing body weight and, of note, in resisting diet-induced obesity. These results reveal a critical role for leptin action on VMH neurons.

BackgroundThe gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism.Scope of reviewIn this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery.Major conclusionsIn recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.

We found that increasing ghrelin levels, through subcutaneous injections or calorie restriction, produced anxiolytic-and antidepressant-like responses in the elevated plus maze and forced swim test. Moreover, chronic social defeat stress, a rodent model of depression, persistently increased ghrelin levels, whereas growth hormone secretagogue receptor (Ghsr) null mice showed increased deleterious effects of chronic defeat. Together, these findings demonstrate a previously unknown function for ghrelin in defending against depressive-like symptoms of chronic stress.Chronic stress induces changes in mood, feeding and metabolism by a poorly understood neurobiological mechanism. Recent studies have suggested that key metabolic signals may interact with CNS circuits to regulate reward and mood 1 . To further explore these links, we investigated the potential role of ghrelin, an important feeding peptide, in the development of depressive symptoms. Ghrelin is a hormone synthesized predominantly by specialized gastrointestinal endocrine cells and is released during periods of negative energy balance 2 . In response to energy insufficiency, ghrelin induces a potent feeding response via activation of the growth hormone secretagogue receptor (GHSR, ghrelin receptor) 2,3 .To determine whether ghrelin can affect mood symptoms, we physiologically increased ghrelin levels by restricting the food intake of mice with a diet containing 60% of normal calories for Fig. 1). This resulted in a fourfold increase in circulating levels of acylated ghrelin (calorie restricted wild-type mice: 7.93 ± 1.59 pg mL −1 , n = 6; wildtype mice fed ad libitum: 1.98 ± 0.37 pg mL −1 , n = 5; P < 0.01). Calorie-restricted wild-type mice showed robust anxiolytic-and antidepressant-like behavior in the elevated plus maze (EPM) and forced swim test (FST), respectively, as compared with wild-type mice fed ad libitum (controls; Fig. 1a,c). In contrast, genetic blockade of ghrelin signaling in Ghsr −/− mice negated these calorie restriction-associated anxiolytic-and antidepressant-like effects. Further analyses demonstrated that the observed differences between the two genotypes cannot be attributed to differences in sensorimotor coordination, general locomotor activity or body weight ( Supplementary Figs. 1-3 online).We used a pharmacologic approach to extend our food-restriction results. We subcutaneously injected C57BL6/J mice with a dose of ghrelin that induces potent feeding (Fig. 1f) and tested them in the EPM and FST 45 min later. Mice receiving ghrelin demonstrated significantly less anxiety-and depression-like symptoms in these tests compared with saline-injected controls (Fig. 1b,d).Next, we determined whether ghrelin signaling regulates depressive symptoms in a mouse model of chronic stress. We used the chronic social defeat stress (CSDS) procedure, which subjects mice to ten daily bouts of social defeat by aggressive CD1 male mice 1,4 (Fig. 2). Mice subjected to CSDS showed lasting behavioral deficits, including social avoidance ( Suppl...