Ghrelin mimics fasting to enhance human hedonic, orbitofrontal cortex, and hippocampal responses to food

Abstract

Background: Ghrelin, which is a stomach-derived hormone, increases with fasting and energy restriction and may influence eating behaviors through brain hedonic reward-cognitive systems. Therefore, changes in plasma ghrelin might mediate counter-regulatory responses to a negative energy balance through changes in food hedonics.

Objective: We investigated whether ghrelin administration (exogenous hyperghrelinemia) mimics effects of fasting (endogenous hyperghrelinemia) on the hedonic response and activation of brain-reward systems to food.

Design: In a crossover design, 22 healthy, nonobese adults (17 men) underwent a functional magnetic resonance imaging (fMRI) food-picture evaluation task after a 16-h overnight fast (Fasted-Saline) or after eating breakfast 95 min before scanning (730 kcal, 14% protein, 31% fat, and 55% carbohydrate) and receiving a saline (Fed-Saline) or acyl ghrelin (Fed-Ghrelin) subcutaneous injection before scanning. One male subject was excluded from the fMRI analysis because of excess head motion, which left 21 subjects with brain-activation data.

Results: Compared with the Fed-Saline visit, both ghrelin administration to fed subjects (Fed-Ghrelin) and fasting (Fasted-Saline) significantly increased the appeal of high-energy foods and associated orbitofrontal cortex activation. Both fasting and ghrelin administration also increased hippocampus activation to high-energy- and low-energy-food pictures. These similar effects of endogenous and exogenous hyperghrelinemia were not explicable by consistent changes in glucose, insulin, peptide YY, and glucagon-like peptide-1. Neither ghrelin administration nor fasting had any significant effect on nucleus accumbens, caudate, anterior insula, or amygdala activation during the food-evaluation task or on auditory, motor, or visual cortex activation during a control task.

Conclusions: Ghrelin administration and fasting have similar acute stimulatory effects on hedonic responses and the activation of corticolimbic reward-cognitive systems during food evaluations. Similar effects of recurrent or chronic hyperghrelinemia on an anticipatory food reward may contribute to the negative impact of skipping breakfast on dietary habits and body weight and the long-term failure of energy restriction for weight loss.

FIGURE 1.

Study-visit protocol. Timings of blood sampling and VAS ratings and detail of scanning, including food picture and AMV fMRI runs and anatomical T1. AMV, auditory-motor-visual; T1, T1 MRI brain scan; VAS, visual analog scale.

FIGURE 2.

Mean (±SEM) food-appeal ratings at study visits. Appeal rating of food pictures (1 = not at all; 5 = a lot) at Fasted-Saline, Fed-Saline, and Fed-Ghrelin visits for FOOD, HE, and LE (A) and different categories of high-energy foods (chocolate, other sweet, and nonsweet) (B). n = 22. ^#P = 0.057, *P < 0.05, **P < 0.01, ***P < 0.005 compared with Fed-Saline using a 1-factor repeated-measures ANOVA with post hoc Student Newman-Keuls test. Fasted-Saline, 16-h overnight fast and given subcutaneous saline injection; Fed-Ghrelin, given breakfast and subcutaneous ghrelin injection; Fed-Saline, given breakfast and subcutaneous saline injection; FOOD, high- or low-energy foods; HE, high-energy foods; LE, low-energy foods.

FIGURE 3.

Mean (±SEM) group activation of brain-reward systems to food pictures and auditory, motor, and visual cortex during a control task at study visits. Magnitude of group activation (percentage of BOLD signal change) for FOOD, HE, or LE minus object picture contrast at Fasted-Saline, Fed-Saline, and Fed-Ghrelin visits in the bilateral OFC (A), hippocampus (B), nucleus accumbens (C), caudate (D), anterior insula (E), and amygdala (F). Magnitude of group activation to a control auditory task (listening to a story) in the bilateral postSTG, motor task (button press) in the left preCG, and visual task (flashing checkerboard) in the lingual gyrus (G). n = 21 (both sexes). ^#P = 0.08–0.09, *P < 0.05, **P< 0.005 compared with Fed-Saline by using a 1-factor repeated-measures ANOVA with the post hoc Student Newman-Keuls test. Fasted-Saline, 16-h overnight fast and given subcutaneous saline injection; Fed-Ghrelin, given breakfast and subcutaneous ghrelin injection; Fed-Saline, given breakfast and subcutaneous saline injection; FOOD, high- or low-energy foods; HE, high-energy foods; LE, low-energy foods; OFC, orbitofrontal cortex; postSTG, posterior division of the superior temporal gyrus; preCG, precentral gyrus.

FIGURE 4.

Hunger and fullness VASs at study visits. Mean (±SEM) VAS ratings plotted against time for hunger (A) and fullness (C) at Fasted-Saline, Fed-Saline, and Fed-Ghrelin visits. Arrows indicate the time of breakfast (0 min) and subcutaneous injection (+55 min), and the solid bar denotes the time of the MRI scan (from +75 to +135 min). n = 22. Median (IQR) AUC VAS ratings for hunger (B) and fullness (D) at Fasted-Saline, Fed-Saline, and Fed-Ghrelin visits. The preinjection AUC was for the time period from −15 to +55 min (maximum value: 700 cm/min). The postinjection AUC was for the time period from +55 to +150 min and covered the period of the MRI scan (maximum value: 950 cm/min). *P < 0.05 compared with Fasted-Saline for post hoc Student Newman-Keuls test in a 1-factor repeated-measures ANOVA on ranks (both P < 0.001 for the overall ANOVA). n = 22. Bkfast, breakfast; Fasted-Saline, 16-h overnight fast and given subcutaneous saline injection; Fed-Ghrelin, given breakfast and subcutaneous ghrelin injection; Fed-Saline, given breakfast and subcutaneous saline injection; Inject, injection; VAS, visual analog scale.

FIGURE 5.

Blood growth hormone and acyl ghrelin concentrations at study visits. Mean (±SEM) concentrations over time of serum GH (A) and plasma acyl ghrelin (B) at Fasted-Saline, Fed-Saline, and Fed-Ghrelin visits. Arrows indicate the time of breakfast (0 min) and subcutaneous injection (+55 min), and the solid bar denotes the time of the MRI scan (from +75 to +135 min). n = 22. AUC for t1 (from −15 to +40 min) or t2 (from +40 to +150 min). ^††P < 0.01, Fasted-Saline compared with Fed-Saline; ⁺⁺P < 0.01, ⁺⁺⁺P < 0.005, Fed-Ghrelin compared with Fed-Saline; *P < 0.05, ***P < 0.001, Fed-Ghrelin compared with Fasted-Saline (see Supplemental Table 6 under “Supplemental data” in the online issue). Comparisons were made by using a 1-factor repeated-measures Friedman’s ANOVA on ranks with post hoc Student-Newman-Keuls test. Bkfast, breakfast; Fasted-Saline, 16-h overnight fast and given subcutaneous saline injection; Fed-Ghrelin, given breakfast and subcutaneous ghrelin injection; Fed-Saline, given breakfast and subcutaneous saline injection; GH, growth hormone; Inject, injection.