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The neuronal coordination of metabolic homeostasis requires the integration of hormonal signals with multiple interrelated central neuronal circuits to produce appropriate levels of food intake, energy expenditure and fuel availability. Ghrelin, a peripherally produced peptide hormone, circulates at high concentrations during nutrient scarcity. Ghrelin promotes food intake, an action lost in ghrelin receptor null mice and also helps maintain fasting blood glucose levels, ensuring an adequate supply of nutrients to the central nervous system. To better understand mechanisms of ghrelin action, we have examined the roles of ghrelin receptor (GHSR) expression in the mouse hindbrain. Notably, selective hindbrain ghrelin receptor expression was not sufficient to restore ghrelin-stimulated food intake. In contrast, the lowered fasting blood glucose levels observed in ghrelin receptor-deficient mice were returned to wild-type levels by selective re-expression of the ghrelin receptor in the hindbrain. Our results demonstrate the distributed nature of the neurons mediating ghrelin action. Fil: Scott, Michael M.. University of Texas; Estados Unidos. University of Virginia; Estados Unidos Fil: Perello, Mario. University of Texas; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Chuang, Jen Chieh. University of Texas; Estados Unidos Fil: Sakata, Ichiro. University of Texas; Estados Unidos Fil: Gautron, Laurent. University of Texas; Estados Unidos Fil: Lee, Charlotte E.. University of Texas; Estados Unidos Fil: Lauzon, Danielle. University of Texas; Estados Unidos Fil: Elmquist, Joel K.. University of Texas; Estados Unidos Fil: Zigman, Jeffrey M.. University of Texas; Estados Unidos

The hormones leptin and ghrelin act in apposition to one another in the regulation of body weight homeostasis. Interestingly, both leptin receptor expression and ghrelin receptor expression have been observed within many of the same nuclei of the central nervous system (CNS), suggesting that these hormones may act on a common population of neurons to produce changes in food intake and energy expenditure. In the present study we explored the extent of this putative direct leptin and ghrelin interaction in the CNS and addressed the question of whether a loss of ghrelin signaling would affect sensitivity to leptin. Using histological mapping of leptin receptor and ghrelin receptor expression, we found that cells containing both leptin receptors and ghrelin receptors are mainly located in the medial part of the hypothalamic arcuate nucleus. In contrast, coexpression was much less extensive elsewhere in the brain. To assess the functional consequences of this observed receptor distribution, we explored the effect of ghrelin receptor deletion on leptin sensitivity. In particular, the responses of ad libitum-fed, diet-induced obese and fasted mice to the anorectic actions of leptin were examined. Surprisingly, we found that deletion of the ghrelin receptor did not affect the sensitivity to exogenously administrated leptin. Thus, we conclude that ghrelin and leptin act largely on distinct neuronal populations and that ghrelin receptor deficiency does not affect sensitivity to the anorexigenic and body weight-lowering actions of leptin. © 2011 Wiley Periodicals, Inc. Fil: Perello, Mario. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Texas Southwestern Medical Center; Estados Unidos Fil: Scott, Michael M.. University of Texas Southwestern Medical Center; Estados Unidos Fil: Sakata, Ichiro. University of Texas Southwestern Medical Center; Estados Unidos Fil: Lee, Charlotte E.. University of Texas Southwestern Medical Center; Estados Unidos Fil: Chuang, Jen Chieh. University of Texas Southwestern Medical Center; Estados Unidos Fil: Osborne Lawrence, Sherri. University of Texas Southwestern Medical Center; Estados Unidos Fil: Rovinsky, Sherry A.. University of Texas Southwestern Medical Center; Estados Unidos Fil: Elmquist, Joel K.. University of Texas Southwestern Medical Center; Estados Unidos Fil: Zigman, Jeffrey M.. University of Texas Southwestern Medical Center; Estados Unidos

Previous work has demonstrated that the peptide hormone ghrelin raises blood glucose. Such has been attributed to ghrelin's ability to enhance GH secretion, restrict insulin release, and/or reduce insulin sensitivity. Ghrelin's reported effects on glucagon have been inconsistent. Here, both animal- and cell-based systems were used to determine the role of glucagon in mediating ghrelin's effects on blood glucose. The tissue and cell distribution of ghrelin receptors (GHSR) was evaluated by quantitative PCR and histochemistry. Plasma glucagon levels were determined following acute acyl-ghrelin injections and in pharmacological and/or transgenic mouse models of ghrelin overexpression and GHSR deletion. Isolated mouse islets and the α-cell lines αTC1 and InR1G9 were used to evaluate ghrelin's effects on glucagon secretion and the role of calcium and ERK in this activity. GHSR mRNA was abundantly expressed in mouse islets and colocalized with glucagon in α-cells. Elevation of acyl-ghrelin acutely (after sc administration, such that physiologically relevant plasma ghrelin levels were achieved) and chronically (by slow-releasing osmotic pumps and as observed in transgenic mice harboring ghrelinomas) led to higher plasma glucagon and increased blood glucose. Conversely, genetic GHSR deletion was associated with lower plasma glucagon and reduced fasting blood glucose. Acyl-ghrelin increased glucagon secretion in a dosedependent manner from mouse islets and α-cell lines, in a manner requiring elevation of intracellular calcium and phosphorylation of ERK. Our study shows that ghrelin's regulation of blood glucose involves direct stimulation of glucagon secretion from α-cells and introduces the ghrelin-glucagon axis as an important mechanism controlling glycemia under fasting conditions. Fil: Chuang, Jen Chieh. University of Texas. Southwestern Medical Center; Estados Unidos Fil: Sakata, Ichiro. University of Texas. Southwestern Medical Center; Estados Unidos Fil: Kohno, Dasuke. University of Texas. Southwestern Medical Center; Estados Unidos Fil: Perello, Mario. University of Texas. Southwestern Medical Center; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina Fil: Lawrence, Serri Osborne. University of Texas. Southwestern Medical Center; Estados Unidos Fil: Repa, Joyce R.. University of Texas. Southwestern Medical Center; Estados Unidos Fil: Zigman, Jeffrey M. University of Texas. Southwestern Medical Center; Estados Unidos

The popular media and personal anecdotes are rich with examples of stress-induced eating of calorically dense "comfort foods." Such behavioral reactions likely contribute to the increased prevalence of obesity in humans experiencing chronic stress or atypical depression. However, the molecular substrates and neurocircuits controlling the complex behaviors responsible for stress-based eating remain mostly unknown, and few animal models have been described for probing the mechanisms orchestrating this response. Here, we describe a system in which food-reward behavior, assessed using a conditioned place preference (CPP) task, is monitored in mice after exposure to chronic social defeat stress (CSDS), a model of prolonged psychosocial stress, featuring aspects of major depression and posttraumatic stress disorder. Under this regime, CSDS increased both CPP for and intake of high-fat diet, and stress-induced food-reward behavior was dependent on signaling by the peptide hormone ghrelin. Also, signaling specifically in catecholaminergic neurons mediated not only ghrelin's orexigenic, antidepressant-like, and food-reward behavioral effects, but also was sufficient to mediate stress-induced food-reward behavior. Thus, this mouse model has allowed us to ascribe a role for ghrelin-engaged catecholaminergic neurons in stress-induced eating. Fil: Chuang, Jen-Chieh. University of Texas; Estados Unidos Fil: Perello, Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina. University of Texas; Estados Unidos Fil: Sakata, Ichiro. University of Texas; Estados Unidos Fil: Osborne Lawrence, Sherri. University of Texas; Estados Unidos Fil: Savitt, Joseph M.. University Johns Hopkins; Estados Unidos Fil: Lutter, Michael. University of Texas; Estados Unidos Fil: Zigman, Jeffrey M.. University of Texas; Estados Unidos