A number of peptides that are released from the gut according to the energy balance status can then access neuronal cell populations in the brain via the circulation; in the brain, they help to regulate energy and glucose homeostasis. Among those peptides, ghrelin is the only known peripheral signal to potently stimulate food intake. Initially, ghrelin was identified as the endogenous agonist of the growth hormone secretagogue receptor 1a (GHS-R1a), stimulation of which is known to boost growth hormone (GH) secretion.
Since then, however, the number of potential functions for ghrelin has increased rapidly to include control of metabolic, cardiovascular, immunologic, reproductive and behavioral processes as well as gastrointestinal motility. Many of these physiologic processes are affected by obesity, insulin resistance, impaired glucose tolerance and type 2 diabetes as well as by atherosclerosis and dyslipidemia.The frequent association of diabetes with obesity emphasizes the many shared pathophysiologic aspects of these conditions.
In this review, we summarize the current state of research on ghrelin and its receptor(s). In particular, we discuss the role of ghrelin in energy balance and glucose homeostasis, and the potential application of drugs targeting ghrelin signaling, to prevent and treat obesity and diabetes.
The Ghrelin-ghrelin-receptor system
The GHS-R1a is a typical G-protein-coupled receptor, exhibiting seven transmembrane domains, that is mainly expressed in different brain areas but also in the pituitary gland, pancreas, white adipose tissue, gastrointestinal system, cardiovascular tissues, adrenal gland and gonadal issues (reviewed by Nogueiras et al.5). It was identified in 1996, three years before Kangawa and colleagues identified ghrelin as the endogenous ligand for the formerly ‘orphan’ GHS-R1a.Ghrelin is mainly expressed in the stomach, and substantially lower expression, of unclear significance, is found in a variety of organs including the gastrointestinal tract, pancreas, brain, pituitary gland, kidney, lung, heart and placenta.
In the stomach, the native ghrelin peptide consists of 28 amino acids and carries a posttranslational esterification with an acyl residue at Ser3 that is rare in mammalian biology.In humans, several ghrelin-derived peptides have been discovered and are classified into four groups by the type of acylation observed at Ser3:7 des-acylated, octanoylated (C8:0), decanoylated (C10:0), and possibly decenoylated (C10:1). All peptides found were either 27 or 28 amino acids in length, the former lacking the C-terminal Arg28, and are derived from the same ghrelin precursor through two alternative pathways.
Most human ghrelin molecules possess 28 amino acids and carry an octanoyl residue (C8:0). This form is expressed six times as much as the other ghrelin-derived molecules in human stomach.7 The octanoyl residue is essential for binding and activating GHS-R1a. It is not yet known whether the acyl residues are synthesized de novo, or how ingested nutrients influence this process.
Regulation of ghrelin by enegry balance
Ghrelin secretion is pulsatile,and plasma levels peak before meals, suggesting that ghrelin can contribute to meal initiation26 or metabolic preparation for nutrient ingestion. Gastric ghrelin expression and peptide secretion are increased by food deprivation and normalize during refeeding.In addition, high fasting ghrelin levels are reduced by consumption of glucose27 or lipid, but not water, indicating that ghrelin release is regulated by macronutrients, and not simply by distension of the stomach.
Basal ghrelin levels are usually lower in obesity,30 but elevated in patients with anorexia nervosa. The overall plasma ghrelin profile is abnormal in obese individuals: there is absent or muted ghrelin elevation during fasting,lack of the normal nocturnal rise of ghrelin,33 and blunted suppression of ghrelin levels after a meal.It has been suggested that plasma leptin reduces ghrelin levels.
Increased leptin levels in obese patients could, therefore, explain ghrelin dysregulation in obesity.In obese humans, the increase of 24-hour plasma ghrelin levels after weight loss is, however, more reflective of changes in fat-free mass than in fat mass.35 Overall, published data imply that ghrelin is regulated by the nutritional status of the organism and acts to optimize energy metabolism in periods of food shortage as well as preparing the metabolism for optimal perception of incoming meals.
Physiologic functions of ghrelin
Growth hormone secretion
Ghrelin potently stimulates GH secretion, in a dose-dependent manner. In vivo, this action is mediated by modulation of hypothalamic neurons that secrete GH-releasing hormone or somatostatin. The physiologic relevance of endogenous ghrelin for GH secretion is under debate. Pulses of ghrelin secretion are not entrained to GH pulses, and observations in ghrelin-null and GHS-R-null mice indicate a minor, if any, role for ghrelin in the regulation of the GH–IGF-I (insulin-like growth factor 1) axis.
Central ghrelin action profoundly promotes food intake.Chronic exposure to ghrelin leads to progressive weight gain, which is mainly due to an increase in fat mass, and not associated with longitudinal growth.Hypothalamic neurons co-expressing neuropeptide Y (NPY) and agouti-related protein (AgRP) in the arcuate nucleus (ARC) express GHS-R1a and are an important target for ghrelin.
Selectively attenuated GHS-R1a expression in the ARC leads to decreased fat mass40 and the orexigenic actions of ghrelin functionally depend on the presence of NPY and AgRP.Activation of neurons that co-express NPY and AgRP by centrally administered ghrelin reduces hypothalamic melanocortin tone38 by increasing the inverse agonist effect of AgRP on hypothalamic melanocortin receptors and reducing the release of α- and β-melanocyte-stimulating hormone from neurons that express proopiomelanocortin.
In addition, acute orexigenic effects of intracerebroventricular administration of ghrelin are dependent on the presence of the GH receptor. It is unclear how much stomach-derived ghrelin can reach particular neurons in the central nervous system (CNS).Ghrelin expression in the CNS was reported in several (but not all) studies, but expression levels are very low43 and the relevance of CNS-derived ghrelin is still under debate.
Studies in humans and rodents have found a negative correlation between ghrelin and insulin levels.Ghrelin levels correlate positively with insulin sensitivity,70 and each post-meal rise of insulin was shown to be associated with a fall in ghrelin levels. Treatment of healthy young volunteers with ghrelin decreased insulin secretion and caused hyperglycemia.
In a study published in 2006, the influence of ghrelin on glucose homeostasis was uncovered in a double-knockout model targeting leptin and ghrelin. Although deletion of ghrelin in leptin-deficient (ob/ob) mice did not decrease body weight, it improved glucose tolerance and insulin secretion and action. Lower pancreatic expression of uncoupling protein 2 might mediate the improved insulin secretion. Consistently, improved insulin sensitivity was also reported in mice with genetic deletion of GHS-R.
Ghrelin might, therefore, represent a valid drug target for diabetes. Pancreatic ghrelin expression has been reported, but with substantial inconsistencies between publications. Ghrelin was found in glucagon-producing α cells, in insulinproducing β cells76 as well as in newly defined ε cells. It is assumed that pancreatic ghrelin might have mainly paracrine effects.
Ghrelin as a drug target to treat obesity and diabetes
Despite disappointing results as therapeutic agents for impaired longitudinal growth, GH secretagogues were, as mentioned above, critical for the discovery of the ghrelin–GHS-R1a system. At present, the clinical use that ghrelin and GH secretagogues seem to best fulfill is their potential use as reliable provocative tests for the diagnosis of GH deficiency. The failure of ghrelin analogs to be useful for the treatment of short stature is, therefore, becoming eclipsed by the possibility of new approaches to treat obesity, diabetes or wasting syndromes.
Enthusiasm for ghrelin antagonists as possible anti-obesity drugs has been accompanied by skepticism, because ghrelin levels in obesity are already low.2,86,87 Data from animal studies have, moreover, demonstrated that decreased ghrelin action does not always result in a lean and hypophagic phenotype, but depends on the age of the rats or mice, their gender and their diet. Though ghrelin antagonists and vaccination against ghrelin have already been reported to exert significant effects on energy balance in lean and obese adult rats, a hypothetical ghrelin antagonist might show only modest efficacy in humans; this conclusion is based on observations in adult GHS-R-deficient or ghrelin-deficient mice.
Author: Petra Wiedmer, Rubén Nogueiras, Fabio Broglio, David D’Alessio