Ghrelin Mimics Fasting to Enhance Human Hedonic, Orbitofrontal Cortex, and Hippocampal Responses to Food

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.