br Acknowledgements br Introduction Ghrelin

Acknowledgements
Introduction Ghrelin is a potent orexigenic hormone and growth hormone secretagogue mainly derived from the stomach [1], [2], [3], [4], [5]. Other pleiotropic actions of the hormone include those that are glucoregulatory, food reward-enhancing, gastric motility-enhancing, and anti-depressant [6], [7], [8], [9], [10], [11], [12], [13], [14]. Most of these actions of ghrelin occur via engagement of growth hormone secretagogue receptors (GHSRs; ghrelin receptors) expressed within the stat3 inhibitor [15]. Of the two transcripts from the Ghsr gene, GHSR type 1a (GHSR1a, commonly referred to as “GHSR”) is translated into the functional, seven transmembrane, G-protein coupled receptor for ghrelin, whereas the truncated GHSR type 1b (GHSR1b), which results from an unspliced mRNA that terminates at an intronic stop codon, does not bind to ghrelin and has no known intrinsic function other than heterodimerizing with and attenuating the cell surface expression of GHSR1a [15], [16], [17]. The pattern of GHSR expression within mouse, rat, and primate brains has been established by detection of Ghsr mRNA using in situ hybridization histochemistry (ISHH) [15], [18], [19], [20], [21], [22], [23] as well as by other techniques including receptor binding assays, Western blot analysis, reverse transcriptase-polymerase chain reaction (RT-PCR), and ribonuclease protection assay [24], [25], [26], [27], [28], [29], [30], [31], [32]. GHSR expression within the mouse brain also has been mapped using a GHSR-eGFP reporter mouse model [23], although some differences between eGFP expression in that line and GHSR expression as determined using other methods such as ISHH are apparent. Other GHSR reporter mouse models include a GHSR-knockout, in which a lacZ coding sequence replaces the GHSR coding sequence, resulting in β-galactosidase expression in the place of GHSR expression [33], and a GHSR-IRES-tauGFP line [34], although detailed expression analyses have not been published using those models. Altogether, these techniques reveal a composite pattern of brain GHSR expression that includes relatively high levels within several mediobasal hypothalamic (MBH) nuclei including the arcuate nucleus (Arc), as well as the dorsomedial hypothalamus (DMH), ventromedial hypothalamus (VMH), paraventricular hypothalamus (PVH), and ventral premamillary nucleus (PMV). In addition, GHSR expression occurs in several other hypothalamic nuclei, the midbrain [including the ventral tegmental area (VTA) and substantia nigra (SN)], the dorsal vagal complex (DVC), and the hippocampus and amygdala, to name a few. The food intake and glucoregulatory effects mediated by GHSRs in general and by specific brain GHSR subpopulations have been studied by utilizing several genetically-modified rodent models, which include those with global deletion of GHSR expression [27], [35], [36], [37], [38], [39], [40], neuron-specific GHSR deletion [41], or re-expression or deletion of GHSR expression within selective neuronal subpopulations including those expressing Agouti-related protein (AgRP), Phox2b, or tyrosine hydroxylase [8], [42], [43], [44], [45]. Of all the actions mediated through GHSRs, one of the most robust and well-characterized is the induction of an acute feeding response after peripheral or central administration of ghrelin [3], [4], [36], [42], [46], [47]. However, the orexigenic function of endogenous ghrelin under physiological conditions remains less certain. Indeed, in some studies, mice lacking ghrelin, GHSR, or the enzyme ghrelin-O-acyltransferase (GOAT), which allows ghrelin to bind to GHSR, exhibited normal food intake and/or body weight phenotypes or only subtle changes [27], [40], [48], [49], [50], [51]. However, other studies using either genetic or pharmacologic means to disrupt the endogenous ghrelin system suggest that ghrelin plays an important role in the usual feeding and/or body weight responses to certain physiological perturbations, such as following a short-term fast or chronic exposure to high-fat diet [14], [35], [52]. Efforts to resolve any uncertainties in the orexigenic actions of the endogenous ghrelin system, as well as to probe the chemical and electrophysiological properties of GHSR-expressing neurons and the neurocircuitry within which they operate, would benefit from novel mouse models that facilitate their identification and modulation of their activity.