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

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.

Figure 1

Appetite-related sensation changes after erythromycin infusion compared to saline. (A) The increase in hunger ratings was higher after erythromycin infusion in the time period t = 30–40 min (*p < 0.05). (B) The increase in prospective food consumption ratings was higher after erythromycin infusion in the time period t = 30–40 min (*p < 0.05). (C) The decrease in satiety ratings was not significantly different after erythromycin compared to saline infusion in the time period t = 30–40 min (p = 0.21). (D) The decrease in fullness ratings was not significantly different after erythromycin compared to saline infusion in the time period t = 30–40 min (p = 0.34). Data are shown as mean ± SEM.

Figure 2

Plasma hormone and blood glucose changes after erythromycin infusion compared to saline. (A) Plasma octanoylated ghrelin levels decreased after erythromycin infusion, and increased after placebo infusion. The difference between erythromycin and placebo was significant at t = 30, 40, and 50 min (**p < 0.01). (B) Plasma motilin levels decreased after erythromycin infusion, and increased after placebo infusion, but this difference was not significant. (C) Blood glucose levels increased after erythromycin compared to placebo. The difference between erythromycin and placebo was significant at t = 30 (*p < 0.05). (D) Plasma insulin level increased after erythromycin infusion compared to placebo infusion. The difference between erythromycin and placebo was significant at t = 20 and 30 min (**p < 0.01). Data are shown as mean ± SEM.

Figure 3

Differential brain response to erythromycin infusion versus saline in a mask of pre-hypothesized regions of interest. Color bar represents F-values. pACC, perigenual anterior cingulate cortex; AIC, anterior insular cortex; OFC, orbitofrontal cortex.

Figure 4

Blood oxygen level dependent (BOLD) signal change percentage differences between erythromycin and saline infusion in representative brain regions. (A) Dorsal and ventral midbrain, (B) hypothalamus, (C) bilateral anterior insula, (D) bilateral amygdala, (E) bilateral orbital frontal cortex (OFC), (F) bilateral anterior cingulate cortex (ACC). Data are shown as mean ± SEM.

Figure 5

Overview of homeostatic and hedonic brain regions where differential activation by erythromycin compared to saline covaries with differences in hunger ratings (in brown) and hedonic food intake (in blue). pACC, perigenual anterior cingulate cortex; AIC, anterior insular cortex; OFC, orbitofrontal cortex.