Circulating glucose levels modulate neural control of desire for high-calorie foods in humans

Abstract

Obesity is a worldwide epidemic resulting in part from the ubiquity of high-calorie foods and food images. Whether obese and nonobese individuals regulate their desire to consume high-calorie foods differently is not clear. We set out to investigate the hypothesis that circulating levels of glucose, the primary fuel source for the brain, influence brain regions that regulate the motivation to consume high-calorie foods. Using functional MRI (fMRI) combined with a stepped hyperinsulinemic euglycemic-hypoglycemic clamp and behavioral measures of interest in food, we have shown here that mild hypoglycemia preferentially activates limbic-striatal brain regions in response to food cues to produce a greater desire for high-calorie foods. In contrast, euglycemia preferentially activated the medial prefrontal cortex and resulted in less interest in food stimuli. Indeed, higher circulating glucose levels predicted greater medial prefrontal cortex activation, and this response was absent in obese subjects. These findings demonstrate that circulating glucose modulates neural stimulatory and inhibitory control over food motivation and suggest that this glucose-linked restraining influence is lost in obesity. Strategies that temper postprandial reductions in glucose levels might reduce the risk of overeating, particularly in environments inundated with visual cues of high-calorie foods. IntroductionGlucose is an important regulatory signal and the primary fuel source for the brain (1). Specialized glucose-sensing neurons located in the hypothalamus, hindbrain, and forebrain are important in the control of glucose homeostasis and feeding behavior (1, 2). Transient declines in blood glucose increase hunger and therefore mobilize an individual toward food consumption (3, 4), particularly high-sugar (5) and high-fat foods (6). Further, hypoglycemia provokes a physiological stress response to mobilize the individual toward seeking food and restoring glucose levels (6). While the role of hindbrain and hypothalamic neuronal responses in hypoglycemia and maintaining energy homeostasis is well characterized (1, 2, 7), the specific neural mechanisms mediating the motivational drive for food under mild hypoglycemic conditions are not known. We hypothesized that a reduction in circulating glucose, to levels commonly observed several hours after glucose ingestion in healthy individuals (8), would activate brain reward and motivation pathways, including the striatum and insula, while concomitantly increasing desire for high-calorie foods.To test this hypothesis, we performed functional MRI (fMRI) studies in 14 healthy (9 nonobese and 5 obese) subjects 2 hours after ingestion of a standardized lunch. Subjects viewed high-calorie food, low-calorie food, and non-food images while lying in the scanner during a stepped hyperinsulinemic euglycemic-hypo-

Liraglutide Reduces CNS Activation in Response to Visual Food Cues Only After Short-term Treatment in Patients With Type 2 Diabetes

“…These lower glucose levels with liraglutide are, however, unlikely to explain our results, as lower circulating levels of glucose are associated with increased activation in insula and putamen during the viewing of food pictures (38). Despite the slightly lower glucose levels with liraglutide treatment in the current study, we observed a decreased CNS activation in insula and putamen.…”

Hypoglycemia unawareness in type 1 diabetes suppresses brain responses to hypoglycemia

“…The caudate has direct physical and functional connections with executive control regions in the frontal cortex including the medial, ventral, and dorsolateral PFC (22,23). Among HC individuals, mild hypoglycemia was sufficient to elicit changes in the caudate, cortical regions such as the vmPFC and vlPFC, and the insula, which is consistent with previous studies that have shown that the caudate, PFC, and insula are responsive to changes in circulating glucose levels (5,12,24,25). In contrast, T1DM-Aware individuals had altered patterns of cortico-striatal activity with no significant changes in the caudate or insula during hypoglycemia.…”

“…We have previously reported using the glucose clamp technique together with functional magnetic resonance (fMRI) imaging, visual food cues, and behavioral measures that brain regions involved in stimulating motivation to eat are exquisitely sensitive to small reductions in glucose. In healthy humans, mild reductions in plasma glucose (~68 mg/dl) that were not sufficient to increase counterregulatory hormones were sufficient to activate hypothalamic blood flow (4) as well as modulate brain motivation/reward and executive control responses to food cues, which in turn resulted in a greater craving for high-calorie foods (5).…”

The role of neural impulse control mechanisms for dietary success in obesity

“…A variety of factors in the development and maintenance of obesity are currently discussed, including psychological (e.g., Weygandt et al, 2012;Rothemund et al, 2007;Torres et al, 2007;Ng & Jeffrey, 2003;Rodin et al, 1989), behavioural (e.g., Hays et al, 2008;Bellisle et al, 2004), genetic (e.g., Dina et al, 2007;Frayling et al, 2007), and endocrinological (e.g., Page et al, 2011;Ahima, 2008;Rosenbaum et al, 2008;Farooqi et al, 2007;Klok et al, 2007). Within the latter framework, also (insufficient) cerebral insulin suppression during stressful events is discussed, a topic especially referred to in the literature on the 'selfish-brain theory' (c.f.…”