The motilin receptor agonist erythromycin stimulates hunger and food intake through a cholinergic pathway

Abstract

Background: Motilin-induced phase III contractions have been identified as a hunger signal. These phase III contractions occur as part of the migrating motor complex (MMC), a contractility pattern of the gastrointestinal tract during fasting. The mechanism involved in this association between subjective hunger feelings and gastrointestinal motility during the MMC is largely unknown, however, as is its ability to stimulate food intake. Objectives: We sought to 1) investigate the occurrence of hunger peaks and their relation to phase III contractions, 2) evaluate whether this relation was cholinergically driven, and 3) assess the ability of the motilin receptor agonist erythromycin to induce food intake. Design: An algorithm was developed to detect hunger peaks. The association with phase III contractions was studied in 14 healthy volunteers [50% men; mean 6 SEM age: 25 6 2 y; mean 6 SEM body mass index (BMI; in kg/m 2 ): 23 6 1]. The impact of pharmacologically induced phase III contractions on the occurrence of hunger peaks and the involvement of a cholinergic pathway were assessed in 14 healthy volunteers (43% men; age: 29 6 3 y; BMI: 23 6 1). Last, the effect of erythromycin administration on food intake was examined in 15 healthy volunteers (40% men; age: 28 6 3 y; BMI: 22 6 1). Results: The occurrence of hunger peaks and their significant association with phase III contractions was confirmed (P , 0.0001). Pharmacologically induced phase III contractions were also significantly associated with hunger peaks (P , 0.05), and this association involved a cholinergic pathway. Administering erythromycin significantly stimulated food intake compared with placebo (53% 6 13% compared with 10% 6 5%; P , 0.05). Conclusions: Motilin-induced phase III contractions induced hunger feelings through a cholinergic pathway. Moreover, erythromycin stimulated food intake, suggesting a physiologic role of motilin as an orexigenic signal from the gastrointestinal tract. This trial was registered at www.clinicaltrials.gov as NCT02633579.Am J Clin Nutr 2016;103:730-7.

The motilin agonist erythromycin increases hunger by modulating homeostatic and hedonic brain circuits in healthy women: a randomized, placebo-controlled study

“…In the present study, we replicated the hunger-inducing effect of the motilin agonist erythromycin found in previous studies in healthy female volunteers by our group 7 , 8 . Further, we demonstrated for the first time that this leads to increased hedonic food intake 50 minutes after the start of the infusion (although it should be noted that only a non-significant trend was found, which may be due to the late administration of the test relative to infusion, see below).…”

“…Regarding the stimulatory effect of a low dose of erythromycin on hunger and prospective food consumption ratings, we confirmed previous work by our group 7 , 8 . In line with these effects on subjective ratings, there was a trend towards more hedonic food intake after erythromycin infusion compared to placebo, with a small effect size (Cohen’s d : 0.44).…”

“…infusion of a low dose (40 mg) of erythromycin induces gastric phase III contractions accompanied by peaks in hunger ratings, not only after prolonged fasting but also in the interprandial state (120 minutes after a 250 kcal meal). Moreover, subjects requested a meal more often after erythromycin administration compared to placebo 7 . Cholinergic blockade by atropine suppressed both gastric phase III contractions and hunger peaks associated wih erythromycin administration.…”

“…Phase III is characterized by strong contractile activity. In healthy humans, gastric but not duodenal phase IIIs are preceded by a motilin peak and exogenous administration of motilin induces a premature gastric phase III 5 , 6 , which has recently been associated with increases in hunger ratings and with the occurrence of hunger peaks during fasting 7 .…”

Intragastric infusion of denatonium benzoate attenuates interdigestive gastric motility and hunger scores in healthy female volunteers

“…Endogenous motilin 52 plasma levels, but not ghrelin, fluctuate in synchrony with antral contractility of the MMC, to 53 reach a peak just before the occurrence of a gastric phase III (16,17,19). We recently showed 54 that motilin-induced gastric phase III contractions of the MMC signal hunger in healthy 55 volunteers and that motilin plasma levels were closely associated with interdigestive hunger 56 ratings (20,21). In 1916, Carlson (22) reported an inhibitory effect of intragastrically 57 administered bitter compounds on both fasting gastric contractility and hunger sensations, 58 but the underlying mechanism was not elucidated.…”