Essential Function of Ghrelin in Chronic Starvation

Ghrelin, an octanoylated peptide hormone secreted from the stomach, stimulates the release of growth hormone (GH) from the pituitary. Ghrelin O-acyltransferase (GOAT) is the enzyme required for the attachment of octanoate to serine-3 of ghrelin, a step essential for making active ghrelin. In this study, we eliminated the Goat gene from mice to produce Goat –/– mice that lack octanoylated ghrelin. These mice were indistinguishable in weight from their wild-type (WT) littermates in when fed either a normal or a high fat diet. On 60% calorie restriction, WT and Goat –/– mice lost 30% of their body weight and 75% of their body fat within the first 4 days. While fasting blood glucose levels declined at the same rate initially in WT and Goat –/– mice, levels in the WT mice stabilized at 58–76 mg/dL after 4 days of 60% calorie restriction. In contrast, fasting blood glucose levels in the calorie restricted Goat –/– mice continued declining to 12–36 mg/dL by day 7, at which point the mice were moribund. Levels of ghrelin and GH rose progressively in WT mice during the calorie restriction. GH levels in Goat –/– mice, which have no ghrelin, rose to a much lesser degree, a phenotype also seen in calorie restricted Preproghrelin –/– mice that lack both ghrelin and des-acyl ghrelin. Restoring ghrelin or GH via an osmotic minipump to calorie restricted Goat –/– mice rescued their hypoglycemia. Thus, ghrelin is essential for survival during severe calorie restriction by elevating GH levels to preserve blood glucose and maintain life. The decreased elevation of GH in calorie restricted Goat –/– mice was associated with decreased plasma levels of two gluconeogenic substrates: pyruvate and lactate. Injections of exogenous pyruvate, lactate, and alanine to calorie restricted Goat –/– mice prevented the development of hypoglycemia. Injections of exogenous octanoate to calorie restricted Goat –/– mice, which spares the need to oxidize glucose and gluconeogenic substrate in the tricarboxylic (TCA) cycle to provide energy for gluconeogenesis, also prevented the hypoglycemia. Therefore, the preservation of blood glucose during calorie restriction by the ghrelin-mediated rise in GH involves the maintenance of adequate plasma levels of gluconeogenic substrates. The dramatic rise in plasma ghrelin during chronic severe calorie deprivation is essential to maintain life. However, the mechanism for this increase is not understood. From tissue culture cells derived from mice bearing ghrelinomas induced by a tissue-specific SV40 T-antigen transgene, we found that ghrelin secreting cells express high levels of mRNA encoding the β1-adrenergic receptor. Ghrelin secretion from these cells was stimulated by the addition of norepinephrine or epinephrine, an effect blocked by atenolol, a selective β1-adrenergic antagonist. Treating WT mice with atenolol or reserpine, a drug that depletes adrenergic neurotransmitters from sympathetic neurons, blocked the fasting-induced increase in plasma ghrelin. Thus, ghrelin secretion during fasting is induced by adrenergic agents released by sympathetic neurons which act directly on β1 receptors on the ghrelin-secreting cells of the stomach.