Combined Loss of Ghrelin Receptor and Cannabinoid CB1 Receptor in Mice Decreases Survival but does not Additively Reduce Body Weight or Eating.

Ghrelin administration increases food intake, body weight (BW), adiposity, and blood glucose. In contrast, although mouse models lacking ghrelin or its receptor (Growth Hormone Secretagogue Receptor (GHSR)) exhibit life-threatening hypoglycemia in starvation-like states, they do not exhibit appreciable reductions in food intake, BW, adiposity, blood glucose, or survival when food availability is unrestricted. This suggests the existence of a parallel neuromodulatory system that can compensate for disruptions in the ghrelin system in certain settings. Here, we hypothesized that the cannabinoid CB1 receptor (CB1R) may encode this putative redundancy, and as such, that genetic deletion of both GHSR and CB1R would exaggerate the metabolic deficits associated with deletion of GHSR alone. To test this hypothesis, we assessed food intake, BW, blood glucose, survival, and plasma acyl-ghrelin in ad libitum-fed male wild-type mice and those that genetically lack GHSR (GHSR-nulls), CB1R (CB1R-nulls), or both GHSR and CB1R (double-nulls). BW, fat mass, and lean mass were similar in GHSR-nulls and wild-types, lower in CB1R-nulls, but not further reduced in double-nulls. Food intake, plasma acyl-ghrelin, and blood glucose were similar among genotypes. Deletion of either GHSR or CB1R alone did not have a statistically-significant effect on survival, but double-nulls demonstrated a statistical trend towards decreased survival (p = 0.07). We conclude that CB1R is not responsible for the normal BW, adiposity, food intake, and blood glucose observed in GHSR-null mice in the setting of unrestricted food availability. Nor is CB1R required for plasma acyl-ghrelin secretion in that setting. However, GHSR may be protective against exaggerated mortality associated with CB1R deletion.

Ghrelin Receptor Agonist Rescues Excess Neonatal Mortality in a Prader-Willi Syndrome Mouse Model.

In the current study, we sought to determine the significance of the ghrelin system in Prader-Willi Syndrome (PWS). PWS is characterized by hypotonia and difficulty feeding in neonates and hyperphagia and obesity beginning later in childhood. Other features include low GH, neonatal hypoglycemia, hypogonadism, and accelerated mortality. Although the hyperphagia and obesity in PWS have been attributed to elevated levels of the orexigenic hormone ghrelin, this link has never been firmly established, nor have ghrelin's potentially protective actions to increase GH secretion, blood glucose, and survival been investigated in a PWS context. In the current study, we show that placing Snord116del mice modeling PWS on ghrelin-deficient or ghrelin receptor [GH secretagogue receptor (GHSR)]-deficient backgrounds does not impact their characteristically reduced body weight, lower plasma IGF-1, delayed sexual maturation, or increased mortality in the period prior to weaning. However, blood glucose was further reduced in male Snord116del pups on a ghrelin-deficient background, and percentage body weight gain and percentage fat mass were further reduced in male Snord116del pups on a GHSR-deficient background. Strikingly, 2 weeks of daily administration of the GHSR agonist HM01 to Snord116del neonates markedly improved survival, resulting in a nearly complete rescue of the excess mortality owing to loss of the paternal Snord116 gene. These data support further exploration of the therapeutic potential of GHSR agonist administration in limiting PWS mortality, especially during the period characterized by failure to thrive.

Ghrelin mediates exercise endurance and the feeding response post-exercise.

OBJECTIVE: Exercise training has several well-established health benefits, including many related to body weight, appetite control, and blood glucose homeostasis. However, the molecular mechanisms and, in particular, the hormonal systems that mediate and integrate these beneficial effects are poorly understood. In the current study, we aimed to investigate the role of the hormone ghrelin and its receptor, the growth hormone secretagogue receptor (GHSR; ghrelin receptor), in mediating the effects of exercise on food intake and blood glucose following exercise as well as in regulating exercise endurance capacity. METHODS: We used two mouse models of treadmill running to characterize the changes in plasma ghrelin with exercise. We also assessed the role of the ghrelin system to influence food intake and blood glucose after exercise, exercise endurance, and parameters potentially linked to responses to exercise. Mice lacking GHSRs (GHSR-null mice) and wild-type littermates were studied. RESULTS: An acute bout of exercise transiently elevated plasma acyl-ghrelin. Without the action of this increased ghrelin on GHSRs (as in GHSR-null mice), high intensity interval exercise markedly reduced food intake compared to control mice. The effect of exercise to acutely raise blood glucose remained unmodified in GHSR-null mice. Exercise-induced increases in plasma ghrelin positively correlated with endurance capacity, and time to exhaustion was reduced in GHSR-null mice as compared to wild-type littermates. In an effort to mechanistically explain their reduced exercise endurance, exercised GHSR-null mice exhibited an abrogated sympathoadrenal response, lower overall insulin-like growth factor-1 levels, and altered glycogen utilization. CONCLUSIONS: Exercise transiently increases plasma ghrelin. GHSR-null mice exhibit decreased food intake following high intensity interval exercise and decreased endurance when submitted to an exercise endurance protocol. These data suggest that an intact ghrelin system limits the capacity of exercise to restrict food intake following exercise, although it enhances exercise endurance.

ß1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals.

Ghrelin is an orexigenic gastric peptide hormone secreted when caloric intake is limited. Ghrelin also regulates blood glucose, as emphasized by the hypoglycemia that is induced by caloric restriction in mouse models of deficient ghrelin signaling. Here, we hypothesized that activation of ß1-adrenergic receptors (ß1ARs) localized to ghrelin cells is required for caloric restriction-associated ghrelin release and the ensuing protective glucoregulatory response. In mice lacking the ß1AR specifically in ghrelin-expressing cells, ghrelin secretion was markedly blunted, resulting in profound hypoglycemia and prevalent mortality upon severe caloric restriction. Replacement of ghrelin blocked the effects of caloric restriction in ß1AR-deficient mice. We also determined that treating calorically restricted juvenile WT mice with beta blockers led to reduced plasma ghrelin and hypoglycemia, the latter of which is similar to the life-threatening, fasting-induced hypoglycemia observed in infants treated with beta blockers. These findings highlight the critical functions of ghrelin in preventing hypoglycemia and promoting survival during severe caloric restriction and the requirement for ghrelin cell-expressed ß1ARs in these processes. Moreover, these results indicate a potential role for ghrelin in mediating beta blocker-associated hypoglycemia in susceptible individuals, such as young children.