Gastric vagal afferents (GVAs) play an important role in appetite regulation. Endocannabinoids (ECs) regulate food intake via cannabinoid 1 (CB1) receptors, however, they are also endogenous ligands for transient receptor potential 1 (TRPV1). TRPV1 and CB1 are expressed on GVAs and CB1 is expressed on gastric ghrelin cells. Further, the EC anandamide (AEA) is expressed in the stomach. We determined the relationship between TRPV1, CB1, ghrelin and ECs in GVA signalling in lean and high fat diet (HFD)-induced obese mice.
Male C57BL/6 mice (8wk old) were fed (12wks) a standard laboratory diet (SLD;N=42) or HFD (N=40). An in vitro GVA preparation was used to assess methAEA (mAEA) effects on GVA responses to 3g stretch in the absence and presence of a CB1 (rimonabant;300nM)), TRPV1 (AMG9810;30nM), growth hormone secretagogue receptor (YIL-781;100nM), protein kinase (PK)A (Fragment(6-22)amide:(F6-22);5nM), PKC (bisindolylmaleimide-II:(BIS-II);10nM), Gαi/o (NF023;300nM), or Gαq (YM254890;100nM) antagonist.
SLD mice: low (1-10nM) and high doses (30-100nM) of mAEA reduced and increased responses to 3g stretch respectively; dual effects were reduced in the presence of rimonabant and AMG9810. YIL-781, F6-22 and NF023 prevented the inhibitory and BIS-II and YM254890 reduced the excitatory effects of mAEA.
HFD mice: mAEA (1-100nM) reduced GVA responses to 3g stretch; an effect blocked by rimonabant, AMG9810, YIL-781, NF023, or F6-22.
Conclusion: ECs, acting through CB1 and TRPV1, have a pivotal role in modulating GVA satiety signals depending on the second messenger pathway utilised. In HFD-mice only an inhibitory effect is observed. These changes may contribute to the development and/or maintenance of obesity.