Ghrelin Receptor

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Ghrelin is an octanoylated 28-amino acid, gut-secreted neuroendocrine peptide that integrates energy homeostasis and body growth.26-28 Ghrelin signals the brain by binding to a GPCR, the growth hormone secretagogue receptor (GHSR), to increase metabolic efficiency by stimulating the orexigenic neuropeptide Y (NPY)-AGRP pathway. GHSR is expressed in the anterior pituitary and various hypothalamic and thalamic nuclei.29 As the first circulating hormone known to stimulate food intake in humans, ghrelin has generated significant interest. Its infusion acutely enhances appetite and increases food consumption,30 and elevated levels of circulating ghrelin are characteristic of Prader-Willi Syndrome,31 in which patients exhibit insatiable appetites.32 In healthy individuals, endogenous plasma ghrelin levels rise before meals or upon fasting and decline postprandially,3334 thereby suggesting a complementary relationship with leptin.3536 Infusion of ghrelin into rodents increases feeding and weight gain and decreases energy expenditure.37 Weight gain resulting from chronic administration of ghrelin has been shown to be the consequence of reduced fat utilization and the fact that ghrelin is adipogenic.38

Intercerebroventricular (ICV) administration of anti-ghrelin IgG into rats suppresses feeding in both acute and chronic models.37 Further evidence that ghrelin antagonism leads to weight reduction derives from rodents lacking GHSR.39 Ghrelin receptor-knockout mice weigh 10% less than their wild-type littermates, although ghrelin-knockout mice exhibit no overt phenotype.40 In addition, transgenic rats expressing GHSR antisense mRNA specifically in the ARC weigh 10% less and have 80% less fat than their wild-type counterparts by 3 months of age.41

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