Abstract
The ultimate goal of this research was to find central biomarkers of satiety, i.e., physiological measures in the brain that relate to subjectively rated appetite, actual food intake, or both. This thesis describes the changes in brain activity in response to food stimuli as measured by functional MRI, with a
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focus on the hypothalamus. The hypothalamus is a brain area of particular interest because of its central role in the regulation of food intake. Two earlier studies showed that one long fMRI-scan can be used to measure fMRI signal changes in the hypothalamus in response to the ingestion of a glucose solution. In effect, these studies provided an experimental design suited for the measurement of temporal changes in hypothalamic activity following a single treatment. We aimed to evaluate the use of such fMRI measurements of the hypothalamus as a biomarker of metabolic satiety. First, we showed a prolonged and, importantly, dose-dependent decrease in the hypothalamic fMRI signal within few minutes after the ingestion of a glucose solution. Next, this signal decrease proved to be specific to glucose ingestion in so far that no signal decreases were observed in the hypothalamus after ingestion of a non-sweet carbohydrate (maltodextrin solution) and a sweet-tasting solution (aspartame). Compared to ingestion of glucose, the hypothalamic response after infusion of glucose into the bloodstream was smaller and less prolonged. The blood insulin response to ingestion of glucose was also more prolonged than that to infusion of glucose, and was associated with better glucoregulation. Also, correlations were found between the total fMRI response after glucose infusion and the fasting blood insulin concentration and between the total fMRI response after glucose ingestion and subjective ratings of hunger. In patients with type 2 diabetes mellitus, ingestion of glucose was not associated with a decrease in the hypothalamic fMRI signal as it was in healthy control subjects. In one study, the focus was on sensory-specific rather than metabolic satiety effects. The results showed sex differences in the effect of satiation with chocolate on the brain activity associated with tasting chocolate milk in the hypothalamus, ventral striatum and medial prefrontal cortex. In conclusion, the hypothalamic fMRI response to glucose is a reproducible dose-dependent measure. So far, it has proven to be specific to glucose. Its correlation with subjective ratings of hunger after glucose ingestion makes it an interesting candidate-biomarker of metabolic satiety. It is also affected by preabsorptive signals, the fasting blood insulin concentration and pathology (type 2 diabetes mellitus). Taken together, the research in this thesis provides the first steps to much more functional neuroimaging research into the effects of food stimuli on the hypothalamus and the rest of the brain. In general, functional MRI provides valuable and promising tools for investigating the regulation of food intake in the brain. The search for biomarkers of satiety, whether successful or not, provides a better understanding of the physiological mechanisms behind the regulation of food intake and energy balance. Such knowledge can help in preventing and curing obesity.
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