Gastric vagal afferents (GVAs) relay signals to the hindbrain resulting in sensations of fullness and satiety. Endocannabinoids (ECs) regulate food intake via cannabinoid 1 (CB1) receptors, however, they are also endogenous ligands for transient receptor potential 1 (TRPV1) channels. TRPV1 and CB1 are expressed on GVAs and the EC anandamide (AEA) is synthesised in the stomach. The aim of this study was to determine the relationship between TRPV1, CB1 and ECs in GVA signalling in lean and high fat diet (HFD)-induced obese mice.
Eight week old male C57BL/6 mice were fed standard laboratory diet (SLD;N=42) or HFD (N=40) for 12 weeks. 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 (GHSR) (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.
In SLD mice, low (1-10nM) and high doses (30-100nM) of mAEA reduced and increased GVA responses to 3g stretch respectively; dual effects reduced in the presence of rimonabant or AMG9810. YIL-781, F6-22 and NF023 prevented the inhibitory effect of mAEA on GVAs. Conversely, BIS-II and YM254890 reduced the excitatory effect of mAEA on GVAs responses to 3 g stretch. In HFD mice, mAEA (1-100nM) reduced GVA responses to 3g stretch; an effect blocked in the presence of rimonabant, AMG9810, YIL-781, NF023 or F6-22.
In conclusion, ECs, acting through CB1 and TRPV1, either activate or inhibit 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.