Ghrelin as a Survival Hormone

Abstract

Ghrelin administration induces food intake and body weight gain. Based on these actions, the ghrelin system was initially proposed as an antiobesity target. Subsequent studies using genetic mouse models have raised doubts about the role of the endogenous ghrelin system in mediating body weight homeostasis or obesity. However, this is not to say that the endogenous ghrelin system is not important metabolically or otherwise. Here we review an emerging concept in which the endogenous ghrelin system serves an essential function during extreme nutritional and psychological challenges to defend blood glucose, protect body weight, avoid exaggerated depression, and ultimately allow survival.

Keywords: blood glucose; cachexia; ghrelin; hypoglycemia; psychosocial stress; survival.

Figure 1. Components of the ghrelin system

Human ghrelin is predominantly secreted from the P/D1-like (X/A-like in rats and mouse) endocrine cells within the gastric mucosa. The ghrelin gene encodes a 117 amino acid (a.a.) precursor protein – preproghrelin, which yields proghrelin once a signal peptide is cleaved off. A portion of proghrelin is post-translationally acylated (most often octanoylated) at the serine-3 of the mature hormone – a unique reaction catalyzed by the enzyme ghrelin-O-acyltransferase (GOAT) likely within the endoplasmic reticulum of ghrelin cells. The acylated form (and possibly any remaining unacylated form) of the 94-a.a proghrelin are further processed by prohormone convertase 1/3 likley within the golgi, trans-golgi network (TGN) and/or secretory granules to the mature 28-a.a. ghrelin species. Rat and mouse ghrelin differ from human ghrelin by 2 a.a. [Lys(K)-Ala(A) instead of Arg(R)-val(V) at positions 11 and 12]. Acyl-ghrelin is deacylated rather rapidly in the circulation by butyrylcholineesterase (BuChE) or acyl protein thioesterase 1 (APT1) to the unacyl form. Both forms of ghrelin also are degraded by a group of peptidases that remain poorly characterized. While in circulation, ghrelin-reactive immunoglobulins may bind ghrelin, which has been shown to delay its degradation. The biological effects of acyl-ghrelin are mediated by binding growth hormone secretagogue receptors (GHSR), which are expressed in several discrete brain regions and other target tissues. GHSRs also possess acyl-ghrelin-independent actions due to its presumed high constitutive activity. GHSRs also alter the activity of other GPCRs through heterodimerization, which in some cases requires ghrelin binding to the GHSRs. Unacyl-ghrelin does not bind to GHSR, and the receptor(s) mediating its effects are unknown.

Figure 2. Mechanisms by which ghrelin can increase or prevent falls in blood glucose

Caloric restriction induces ghrelin secretion mostly by increasing sympathetic drive onto ghrelin cells and possibly also due to a reduction in the availability of circulating nutrients (such as glucose), and in turn a reduction in the nutrients’ direct effects on ghrelin cells to decrease ghrelin release. The elevated plasma ghrelin modulates several endocrine and neuronal signals to increase and/or prevent falls in blood glucose. These include reduction in insulin secretion by direct or indirect actions on pancreatic β-cells; increase in glucagon secretion by direct or indirect actions on pancreatic α-cells; actions on the brain to increase cortisol secretion, glucagon secretion, and food intake; increase in the release of growth hormone (GH), which in the appropriate setting can induce liver autophagy to presumably supply substrates for gluconeogenesis. The increased plasma glucagon and brain actions of ghrelin also stimulate gluconeogenesis by induction of the expression of hepatic gluconeogenic enzymes.

Figure 3. Ghrelin as a survival hormone

The essential, protective role of ghrelin as a survival hormone becomes apparent during metabolically and psychologically challenging conditions that include caloric restriction, psychosocial stress and cachexia – all of which are associated with increases in plasma ghrelin, presumably from increased ghrelin secretion. The protective roles of ghrelin during these states are summarized as follows: A) Caloric restriction. During short bouts of caloric restriction, ghrelin limits falls in blood glucose, and afterwards mediates rebound hyperphagia. Following slightly longer bouts of caloric restriction, ghrelin mediates food reward behaviors and mediates antidepressant-like and anxiolytic-like behaviors. During more severe/prolonged caloric restriction, ghrelin prevents life-threatening hypoglycemia. Ghrelin also reduces incidence of hypoglycemia in neonates subjected to short bouts of caloric restriction. (The protective effects of ghrelin during exposure to caloric restriction are emphasized by increasing severity of caloric restriction and by young age). B) Psychosocial stress. Following psychosocial stress, ghrelin defends against exaggerated depressive symptoms and increases food reward behaviors including intake of calorically dense food, presumably as a way to more efficiently store energy to thwart any future threats. C) Cachexia. In conditions characterized by cachexia, ghrelin defends against loss of body weight and muscle mass and extends survival.