MEDICA16

Sensing of fatty acids for octanoylation of ghrelin involves a gustatory G-protein

Background: Ghrelin plays a crucial role in regulating energy and glucose homeostasis. The octanoylation at Ser(3) is vital for ghrelin’s biological functions, yet the mechanisms behind this modification remain unclear. This study aimed to investigate the potential involvement of the gustatory G-protein α-gustducin and the free fatty acid receptors GPR40 and GPR120 in the fatty acid sensing mechanisms of ghrelin-producing cells.

Methods: Wild-type (WT) and α-gustducin knockout (gust(-/-)) mice were placed on a glyceryl trioctanoate-enriched diet (OD) for two weeks. We assessed ghrelin levels and gastric emptying. Immunofluorescence staining was used to examine co-localization between GPR40, GPR120, and ghrelin or α-gustducin/α-transducin. The role of GPR120 in mediating the effects of medium and long-chain fatty acids on ghrelin release was studied using the ghrelinoma cell line MGN3-1. The impact of the GPR40 agonist MEDICA16 and the GPR120 agonist grifolic acid on ghrelin release was evaluated both in vitro and in vivo.

Results: The OD significantly increased octanoyl ghrelin levels in the stomachs of WT mice but not in gust(-/-) mice. Gastric emptying was accelerated in WT mice, while gust(-/-) mice showed no such effect. GPR40 was found to co-localize with desoctanoyl ghrelin but not with octanoyl ghrelin, α-gustducin, or α-transducin in the stomach. Conversely, GPR120 co-localized with ghrelin in the duodenum only. In MGN3-1 cells, octanoic acid increased octanoyl ghrelin levels, while α-linolenic acid decreased them; these effects were not blocked by GPR120 siRNA. In vitro, neither MEDICA16 nor grifolic acid affected ghrelin secretion, but oral administration of grifolic acid did lead to increased plasma ghrelin levels.

Conclusion: This study provides the first evidence that α-gustducin is involved in the octanoylation of ghrelin and demonstrates that ghrelin cells can directly sense medium- and long-chain fatty acids. Additionally, GPR120, rather than GPR40, may play a role in the lipid sensing mechanisms of ghrelin cells.