Opposite Regulation of Ghrelin and Glucagon-like Peptide-1 by Metabolite G-Protein-Coupled Receptors

Gut hormones send information about incoming nutrients to the rest of the body and thereby control many aspects of metabolism. The secretion of ghrelin and glucagon-like protein (GLP)-1, two hormones with opposite secretory patterns and opposite actions on multiple targets, is controlled by a limited number of G-protein coupled receptors (GPCRs); half of which recognize and bind dietary nutrient metabolites, metabolites generated by gut microbiota, and metabolites of the host's intermediary metabolism. Most metabolite GPCRs controlling ghrelin secretion are inhibitory, whereas all metabolite receptors controlling GLP-1 secretion are stimulatory. This dichotomy in metabolite sensor function, which is obtained through a combination of differential expression and cell-dependent signaling bias, offers pharmacological targets to stimulate GLP-1 and inhibit ghrelin through the same mechanism.

TrendsThe gut hormones ghrelin and GLP-1 have opposite functions in basically all endocrine and metabolic target organs, as well as opposite secretion patterns in response to food intake.GPCRs that sense nutrients and endogenous metabolites, in general, inhibit ghrelin and stimulate GLP-1 release – as does glucose independent of GPCRs.Triglyceride metabolites inhibit ghrelin secretion through FFA4 (GPR120), but stimulate GLP-1 secretion through FFA1 (GPR40) and the 2-monoacyl glycerol receptor GPR119.The same metabolite GPCRs, for example, the short chain fatty acid receptor FFA2 (GPR43) and the CaSR signal in a context- and cell-dependent manner to inhibit ghrelin release and stimulate GLP-1 release.