Abstract
The motilin agonist, erythromycin, induces gastric phase III of the migrating motor complex, which in turn generates hunger peaks. To identify the brain mechanisms underlying these orexigenic effects, 14 healthy women participated in a randomized, placebo-controlled crossover study. Functional magnetic resonance brain images were acquired for 50 minutes interprandially. Intravenous infusion of erythromycin (40 mg) or saline started 10 minutes after the start of scanning. Blood samples (for glucose and hormone levels) and hunger ratings were collected at fixed timepoints. Thirteen volunteers completed the study, without any adverse events. Brain regions involved in homeostatic and hedonic control of appetite and food intake responded to erythromycin, including pregenual anterior cingulate cortex, anterior insula cortex, orbitofrontal cortex, amygdala, caudate, pallidum and putamen bilaterally, right accumbens, hypothalamus, and midbrain. Octanoylated ghrelin levels decreased, whereas both glucose and insulin increased after erythromycin. Hunger were higher after erythromycin, and these differences covaried with the brain response in most of the abovementioned regions. The motilin agonist erythromycin increases hunger by modulating neurocircuitry related to homeostatic and hedonic control of appetite and feeding. These results confirm recent behavioural findings identifying motilin as a key orexigenic hormone in humans, and identify the brain mechanisms underlying its effect.
Highlights
The bidirectional neural and hormonal communication system between the brain and the gastrointestinal (GI) tract is known as the ‘brain-gut axis’[1]
We demonstrated for the first time that this leads to increased hedonic food intake 50 minutes after the start of the infusion
We showed for the first time that the motilin receptor agonist, erythromycin, exerts its orexigenic effects by modulating the function of homeostatic and hedonic brain regions involved in the control of appetite and food intake, mediated by the brain-gut axis
Summary
The bidirectional neural and hormonal communication system between the brain and the gastrointestinal (GI) tract is known as the ‘brain-gut axis’[1]. Itoh et al.[10] first found that the macrolide antibiotic erythromycin mimics the effect of exogenous motilin on GI contractile activity in dogs. Later, this was observed in humans[10,11] and erythromycin was shown to be an agonist of motilin receptors in the human duodenum and colon[12,13]. Recent studies by our group[4,8] showed that i.v. infusion of a low dose (40 mg) of erythromycin induces gastric phase III contractions accompanied by peaks in hunger ratings, after prolonged fasting and in the interprandial state (120 minutes after a 250 kcal meal). It is conceivable that this orexigenic effect is due to changes in activity in brain circuits involved in the control of appetite and food intake through the gut-brain axis
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