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  • Here we used chemogenetic modulation of


    Here, we used chemogenetic modulation of MBH GHSR neurons to address the role of the endogenous ghrelin system in the normal, hyperphagic response to a short-term fast. Studies demonstrating the requirement of an intact ghrelin-GHSR system for the rebound food intake following fasting have been inconsistent. For instance, fasting-induced rebound food intake was unaltered in mice lacking ghrelin [49] or GHSR [14], [36], but became apparent in GHSR-knockout mice following repetitive fasting [36]. While one approach to immunoneutralize ghrelin did not affect rebound food intake following a fast [90], another reduced food intake [91], as did pharmacological antagonism of GHSRs [14]. While our results here do not prove that an intact, endogenous ghrelin system is required for the usual rebound food intake response to a 24 h fast, they do demonstrate that the activity of GHSR-expressing MBH neurons is required and suggest that any existing parallel feeding circuits that might play a role in the rebound hyperphagic response to fasting are unable to fully compensate for the deficient activity of the MBH GHSR neurons. It also remains to be seen if activity of these neurons is required for normal food intake when food availability is plentiful, a question that could be addressed by chronic DREADD-assisted inhibition of these neurons. In summary, we present a novel Ghsr-IRES-Cre knock-in mouse line. The GHSR Fmoc-Ser(tBu)-OH pattern revealed here by crossing the Ghsr-IRES-Cre to reporter mice appears to be more complete than that apparent from other individual methods. In addition, the reported physiological data achieved by chemogenetic manipulations of the Ghsr-IRES-Cre line suggest that the activity of MBH GHSR neurons is required for the full acute orexigenic response to administered ghrelin, is required for the usual rebound food intake response following a 24 h fast, and is sufficient to induce spontaneous food intake. The Ghsr-IRES-Cre line should serve as a valuable tool in future studies aimed at investigating the functional significance of other populations of ghrelin-responsive/GHSR-expressing neurons and the neuronal circuitries within which they act.
    Acknowledgments This work was supported through an International Research Alliance with the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen, the Diana and Richard C. Strauss Professorship in Biomedical Research, the Mr. and Mrs. Bruce G. Brookshire Professorship in Medicine, the Kent and Jodi Foster Distinguished Chair in Endocrinology, in Honor of Daniel Foster, M.D., and institutional funds from the University of Texas Southwestern Medical Center to J.M.Z., the Hilda and Preston Davis Foundation Postdoctoral Fellowship Program in Eating Disorders Research to B.K.M., and a National Health and Medical Research Council Fellowship and grants to Z.B.A (APP1084344, APP1030037, APP1125690). We thank Prasanna Vijayaraghavan, Nathan Metzger, and Connor Lawrence for technical assistance with animal breeding.
    Introduction Ghrelin is a stomach-derived hormone that acts to stimulate growth hormone (GH) secretion as well as to affect various processes related to eating, body weight and blood glucose regulation [1]. In contrast to most other metabolically-acting gastrointestinal hormones, ghrelin acutely stimulates eating and also induces body weight gain upon repeated administration as a result of its orexigenic actions and its effects to reduce energy expenditure and preserve fat mass [2], [3], [4], [5], [6]. The actions of ghrelin are mediated through the growth hormone secretagogue receptor (GHSR; ghrelin receptor), which is expressed in several brain sites, the pituitary, and several peripheral organs [7], [8], [9]. GHSR activation by ghrelin requires a unique acylation of the hormone that occurs during its synthesis, although unacyl-ghrelin, which has actions via an as-of-yet unknown receptor, also exists in circulation [10], [11], [12]. Opposite to what might be expected based on the effects of administered ghrelin, genetic mouse models lacking ghrelin or GHSR do not demonstrate substantial differences in food intake and body weight when given free access to standard chow diet [13], [14], [15], [16], [17], [18]. As such, an intact endogenous ghrelin system does not appear to be essential to maintain normal energy homeostasis in mice during standard housing conditions – e.g. ad libidum access to standard chow, minimal to absent psychosocial or other types of stress, and lack of forced physical activity.