TRPV1 Desensitization Abolishes Metabolic Effects of Time-Restricted Feeding in Rats

Time-restricted feeding (TRF) can improve metabolic outcomes. Rodents experiencing TRF exhibit an increase in spontaneous locomotor activity before mealtime and show a phase shift in the rhythm of clock gene expression in peripheral organs, particularly in the liver. Because activation of the transient receptor potential vanilloid-1 (TRPV1) channel produces similar beneficial effects on metabolism as TRF, we hypothesized that this channel mediates the metabolic changes induced by TRF. To assess the role of TRPV1 in metabolism and circadian responses, we utilized the agonist resiniferatoxin (RTX), which at a dosage of 20 µg/kg desensitizes TRPV1. After treatment with RTX or its vehicle, adult male rats were exposed to 21 days of TRF during the light phase. RTX-treated rats show some effects of TRF similar to vehicle-treated controls, with increased locomotor activity and body temperature at the beginning of the light phase, decreased body weight gain and food intake relative to ad-libitum-fed controls. However, RTX-treated rats did not show a decrease in VO₂ consumption or an improvement in glucose tolerance induced by TRF. In addition, RTX treatment eliminated the temporal changes in the expression of clock genes Per1 and Rev-Erba in the liver as well as leptin blood levels. In addition, RTX abolished the temporal alterations of the Trb3 gene in the liver, which encodes a protein that negatively modulates insulin signaling without affecting the expression of insulin, Pparα, Pck1, G6pc, or other clock genes in the liver. In conclusion, TRPV1 may participate in the TRF-induced alterations in metabolism, most likely through its regulation of the temporal changes in Per1, Rev-Erba, and Trb3 expressions in the liver, along with leptin secretion.