Inhibition of ghrelin O-acyltransferase attenuates food deprivation-induced increases in ingestive behavior

Abstract

Ghrelin is an orexigenic hormone produced by the stomach in direct proportion to the time since the last meal and has therefore been called a 'hunger signal'. The octanoylation of ghrelin is critical for its orexigenic functions and is dependent upon ghrelin O-acyltransferase (GOAT) catalyzation. The GOAT inhibitor, GO-CoA-Tat, decreases the circulating concentrations of octanoylated ghrelin and attenuates weight gain on a high fat diet in mice. Unlike rats and mice, Siberian hamsters and humans do not increase food intake after food deprivation, but increase food hoarding after food deprivation. In Siberian hamsters, exogenous ghrelin increases ingestive behaviors similarly to 48-56 h food deprivation. Therefore, we tested the necessity of increased ghrelin in food-deprived Siberian hamsters to stimulate ingestive behaviors. To do so we used our simulated natural housing system that allows hamsters to forage for and hoard food. Animals were given an injection of GO-CoA-Tat (i.p., 11 μmol/kg) every 6h because that is the duration of its effective inhibition of octanoylated ghrelin concentrations during a 48 h food deprivation. We found that GO-CoA-Tat attenuated food foraging (0-1h), food intake (0-1 and 2-4h), and food hoarding (0-1h and 2 and 3 days) post-refeeding compared with saline treated animals. This suggests that increased octanoylated ghrelin concentrations play a role in the food deprivation-induced increases in ingestive behavior. Therefore, ghrelin is a critical aspect of the multi-faceted mechanisms that stimulate ingestive behaviors, and might be a critical point for a successful clinical intervention scheme in humans.

Figure 1

Mean circulating plasma concentrations ± S.E. at 6, 12, and 24 h after a single intraperitoneal injection of GOAT inhibitor, GO-CoA-Tat (11 μmol/kg), or saline at light offset of (A) des-acyl ghrelin (pg/ml) and (B) acyl ghrelin (pg/ml). * P<0.05 vs. saline treat animals within time point.

Figure 2

Mean number of wheel rotations ± S.E. at 0–1, 1–2, 2–4, and 4–24 h and 2, 3, and 4 d post-refeeding after 48 h food deprivation in animals that received GO-CoA-Tat (11 μmol/kg) or saline i.p. in (A) free wheel/free food or (B) 10 wheel rotations/pellet foraging treatments. * P<0.05 vs. saline treated animals within time point.

Figure 3

Mean number of food pellets eaten ± S.E. at 0–1, 1–2, 2–4, and 4–24 h and 2, 3, and 4 d post-refeeding after 48 h food deprivation in animals that received GO-CoA-Tat (11 μmol/kg) or saline i.p. in (A) blocked wheel/free food, (B) free wheel/free food or (C) 10 wheel rotations/pellet foraging treatments. * P<0.05 vs. saline treated animals within time point.

Figure 4

Mean number of food pellets hoarded ± S.E. at 0–1, 1–, 2–4, and 4–24 h and 2, 3, and 4 d post-refeeding after 48 h food deprivation in animals that received GO-CoA-Tat (11 μmol/kg) or saline i.p. in (A) blocked wheel/free food, (B) free wheel/free food or (C) 10 wheel rotations/pellet foraging treatments. * P<0.05 vs. saline treated animals within time point.