Pursuing the Mechanisms Underlying Alcohol-Induced Changes in the Ghrelin System: New Insights from Preclinical and Clinical Investigations

Ghrelin is a gastric-derived peptide hormone with demonstrated impact on alcohol intake and craving, but the reverse side of this bidirectional link, i.e., the effects of alcohol on the ghrelin system, remains to be fully established. To characterize the downstream effects of alcohol on the ghrelin system, we examined the following: (1) plasma ghrelin levels across four human laboratory alcohol administration experiments with non-treatment seeking, heavy-drinking participants, (2) expression of ghrelin, ghrelin receptor, and ghrelin-O-acyltransferase (GOAT) genes (GHRL, GHSR, and MBOAT4, respectively) in human post-mortem brain tissue from individuals with alcohol use disorder (AUD) vs. controls, (3) plasma ghrelin levels in Ghsr knockout and wild-type rats following intraperitoneal (i.p.) ethanol administration, (4) effect of ethanol on ghrelin secretion from gastric mucosa cells ex vivo and GOAT enzymatic activity in vitro, and (5) plasma ghrelin levels in rats following i.p. ethanol administration vs. an iso-caloric sucrose solution. Peripheral acyl- and total ghrelin levels significantly decreased following acute ethanol administration in humans. No difference in GHRL, GHSR, and MBOAT4 mRNA expression in the brain was observed between AUD vs. control post-mortem samples. In rats, acyl-ghrelin levels significantly decreased following i.p. ethanol administration in both genotype groups (Ghsr knockout and wild-type), while des-acyl-ghrelin was not affected by ethanol. No effect of ethanol was observed ex vivo on ghrelin secretion from gastric mucosa cells or in vitro on GOAT acylation activity. Lastly, we observed different effects of i.p. ethanol and sucrose solution on acyl- and des-acyl-ghrelin in rats despite administering amounts with equivalent caloric value. Ethanol acutely decreases peripheral ghrelin concentrations in humans and rats, and our findings suggest that this effect does not occur through interaction with ghrelin-secreting gastric mucosal cells, the ghrelin receptor, or the GOAT enzyme. Moreover, this effect does not appear to be proportional to caloric load. Our findings, therefore, suggest that ethanol does not suppress circulating ghrelin through direct interaction with the ghrelin system, or in proportion to the caloric value of alcohol, and may differentially affect ghrelin acylation and ghrelin peptide secretion.