Abstract
ObjectivesPrevious fMRI studies have demonstrated that glucose decreases the hypothalamic BOLD response in humans. However, the mechanisms underlying the CNS response to glucose have not been defined. We recently demonstrated that the slowing of gastric emptying by glucose is dependent on activation of the gut peptide cholecystokinin (CCK1) receptor. Using physiological functional magnetic resonance imaging this study aimed to determine the whole brain response to glucose, and whether CCK plays a central role. Experimental designChanges in blood oxygenation level-dependent (BOLD) signal were monitored using fMRI in 12 healthy subjects following intragastric infusion (250ml) of: 1M glucose+predosing with dexloxiglumide (CCK1 receptor antagonist), 1M glucose+placebo, or 0.9% saline (control)+placebo, in a single-blind, randomised fashion. Gallbladder volume, blood glucose, insulin, and GLP-1 and CCK concentrations were determined. Hunger, fullness and nausea scores were also recorded. Principal observationsIntragastric glucose elevated plasma glucose, insulin, and GLP-1, and reduced gall bladder volume (an in vivo assay for CCK secretion). Glucose decreased BOLD signal, relative to saline, in the brainstem and hypothalamus as well as the cerebellum, right occipital cortex, putamen and thalamus. The timing of the BOLD signal decrease was negatively correlated with the rise in blood glucose and insulin levels. The glucose+dex arm highlighted a CCK1-receptor dependent increase in BOLD signal only in the motor cortex. ConclusionsGlucose induces site-specific differences in BOLD response in the human brain; the brainstem and hypothalamus show a CCK1 receptor-independent reduction which is likely to be mediated by a circulatory effect of glucose and insulin, whereas the motor cortex shows an early dexloxiglumide-reversible increase in signal, suggesting a CCK1 receptor-dependent neural pathway.
Highlights
IntroductionAnimal studies have identified the hypothalamus as a critical region for the regulation of energy balance (Brown and Melzack, 1969; Grossman, 1975), and in man, a number of fMRI studies have reported that oral glucose decreases hypothalamic blood oxygenation level-dependent (BOLD) signal, relative to water (Liu et al, 2000; Smeets et al, 2005a, 2005b, 2007; Vidarsdottir et al, 2007)
Obesity is one of the major public health problems facing the world
Intragastric glucose slowed gastric emptying when compared with water (p = 0.017), and dexloxiglumide abolished this glucose-induced inhibition (p = 0.031), with no difference between the emptying of water and glucose + dex
Summary
Animal studies have identified the hypothalamus as a critical region for the regulation of energy balance (Brown and Melzack, 1969; Grossman, 1975), and in man, a number of fMRI studies have reported that oral glucose decreases hypothalamic BOLD signal, relative to water (Liu et al, 2000; Smeets et al, 2005a, 2005b, 2007; Vidarsdottir et al, 2007) These studies did not investigate the responses of other sub-cortical brain regions to glucose, and the movement of the head during consumption of oral meals induced imaging artefacts that precluded evaluation of the early responses. Detailed imaging of the human brainstem has not been reported and is critical as it is the first relay point responsible for integrating neural signals transmitted from the upper gut via vagal afferent neurons
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