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    • br Disclosure br Ghrelin System The existence of the ghrelin

    2022-01-29


    Disclosure
    Ghrelin System The existence of the ghrelin system has been demonstrated in many species through a variety of biochemical, anatomical, and genetic studies. It is a complex and intricate regulatory system comprised of several peptides, including mature ghrelin and its derivative des-Gln14-ghrelin, unacylated ghrelin, obestatin, and intron 1-ghrelin, receptors such as growth hormone secretagogue receptor (GHSR) and other unknown but necessary receptors, as well as modifying enzyme ghrelin O-acyltransferase (GOAT). The agonists, ghrelin and des-Gln14-ghrelin, were both originally identified from rat gastric extracts.3, 4 Mature ghrelin is a 28 amino colorimetric peptide that shows high sequence homology across mammals, including human, rat, mouse, rhesus monkey, goat, and dog.3, 5, 6, 7, 8 Ghrelin has also been identified in nonmammalian vertebrates, including fish, amphibians, and birds (reviewed in Ref.[9]). Ghrelin is encoded by the ghrelin (GHRL) gene, which, in addition to ghrelin, also encodes the 23 amino acid peptide obestatin. To activate its only known functional receptor, GHSR type 1a (GHSR1a), ghrelin requires the attachment of 8-carbon medium-chain fatty acid, octanoic acid, to its serine 3 residue, a process called octanoylation, a rare posttranslational modification. In 2008, two groups independently reported an enzyme that catalyzed n-octanoyl modification of ghrelin in vitro, and named the enzyme GOAT.11, 12 The optimal temperature and pH range of GOAT are 37–50°C and pH 7–8, respectively. The GHSR has two isoforms, GHSR1a and GHSR1b. Both are rhodopsin-like G protein-coupled receptors (GPCRs) but only GHSR1a is functional in humans, therefore, GHSR1a, also called ghrelin receptor, will be the main focus of this review. Other receptors mediating unacylated ghrelin action, ghrelin receptor-like receptors, have also been proposed but the identities remain elusive so far.
    Ghrelin System and Energy Homeostasis Despite the versatile physiological roles of ghrelin described earlier, it is the regulation of food intake and energy expenditure that have been most extensively studied. In rodents, Nakazato et al. showed that peripheral administration of ghrelin leads to increased food consumption. In addition, acute ghrelin administration increases respiratory quotient and fat deposition. Further studies demonstrated that rodents with i.c.v. injection of ghrelin tend to augment significantly higher plasma GH level, food intake, and body weight gain compared to that of peripheral injection, suggesting that ghrelin/GHSR functions at the hypothalamic level. Similarly, in humans, Wren and colleagues demonstrated that peripheral ghrelin administration induces the sensation of hunger and increases food intake in lean, obese, healthy, and malnourished individuals. Ghrelin acts presynaptically by stimulating the NPY neurons and inhibiting anorexigenic proopiomelanocortin neurons, resulting in the release of NPY and other orexigenic neurotransmitters, antagonizing leptin action. Kroemer et al. showed that in response to palatable food stimuli, the endogenous fasting levels of ghrelin correlate positively with hunger-modulated activity in limbic and paralimbic regions, areas known to be involved in visual processing, taste sensing, and reward. Similar association was also observed in the hypothalamus, amygdala, and prefrontal cortex of women with active anorexia nervosa. Further evidences that the ghrelin system acts as a major factor in the regulation of energy homeostasis come from rodent studies with genetic manipulation of the Ghsr gene. In 2004, Smith's group showed that ghrelin treatment fails to increase food intake in Ghsr knockout mice, as compared with WT littermates. Insulin and leptin levels are reduced with fasting, and this response remains intact in mice lacking the Ghsr. Furthermore, the body weights of congenic adult Ghsr knockout mice (C57BL6J) are modestly lower than WT controls when they are fed a normal chow diet. In 2005, Zigman et al. demonstrated that mice of mixed genetic background (C57BL6J:129sv) are relatively resistant to diet-induced obesity. In addition, Chen et al. demonstrated that NPY and Agouti-related peptide, well-known potent orexigenic peptides, are essential to mediate the appetite-stimulating effects of ghrelin since mice lacking both NPY and Agouti-related peptide fail to increase food intake following peripheral ghrelin injection. Additionally, recent studies showed that the endocannabinoid system might also mediate the orexigenic effects of ghrelin.