Circulating glucose levels modulate neural control of desire for high-calorie foods in humans
Open accessAbstract
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.
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Simultaneously, hunger and cravings for high-GL foods increase, setting the stage for a vicious cycle.
“Simultaneously, hunger and cravings for high-GL foods (i.e., those that rapidly raise blood glucose) increase, setting the stage for a vicious cycle.”
From The carbohydrate-insulin model: A physiological perspective on the obesity pandemic (2021) · cites this paper as [22]
Experimentally reducing blood glucose to mild hypoglycemic levels relative to normal euglycemic levels increases plasma cortisol and increases wanting of highly palatable foods and brain activation of reward-motivational and emotion-stress regions in response to high-fat, high-sugar highly palatable versus low-fat and non-food pictures.
“experimentally reducing blood glucose to mild hypoglycemic levels relative to normal euglycemic levels, not only increases plasma cortisol but also increases wanting of HP foods and brain activation of reward-motivational (striatal) and emotion-stress (limbic) regions in response to high fat, high sugar HP versus low fat and non-food pictures”
From Role of addiction and stress neurobiology on food intake and obesity (2018) · cites this paper as Page et al., 2011
Higher cortisol responses in the hypoglycemic state were associated with higher striatal-limbic brain activation during concurrent assessment.
“higher cortisol responses in the hypoglycemic state was associated with higher striatal-limbic brain activation during concurrent assessment of these responses”
From Role of addiction and stress neurobiology on food intake and obesity (2018) · cites this paper as Page et al., 2011
The decline in blood glucose (and other metabolic fuels) in the late postprandial period after a high-GI meal increases the hedonic value of food through striatal activation.
“but also increase the hedonic value of food through striatal activation (18).”
From Effects of dietary glycemic index on brain regions related to reward and craving in men (2013) · cites this paper as [18]
In a study of lean and obese adults, a mean insulin-induced decrease in blood glucose concentrations from 4.9 to 3.7 mmol/L increased the food-stimulus activation of the striatum and desire for high-calorie foods.
“Indeed, in a study of lean and obese adults, a mean insulininduced decrease in blood glucose concentrations from 4.9 to 3.7 mmol/L increased the food-stimulus activation of the striatum and desire for high-calorie foods (18).”
From Effects of dietary glycemic index on brain regions related to reward and craving in men (2013) · cites this paper as [18]
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- Authors
- Page, K. A., Seo, D., Belfort-DeAguiar, R., Lacadie, C., Dzuira, J., Naik, S., Amarnath, S., Constable, R. T., Sherwin, R. S., & Sinha, R.
- Affiliations
- Yale University (US)
- Corresponding author
- Sherwin, Robert S.
- Venue
- Journal of Clinical Investigation
- Published
- 2011-10-03
- Volume
- 121
- Issue
- 10
- Pages
- 4161-4169
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3195474
- OpenAlex
- W2141331973
- Cited by
- 212
- References
- 46
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 14 · 2023: 10 · 2022: 12 · 2021: 13 · 2020: 6 · 2019: 22 · 2018: 23 · 2017: 21 · 2016: 15 · 2015: 14 · 2014: 17 · 2013: 15 · 2012: 15
- FWCI
- 6.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Yale University
- National Institutes of Health (P30 DK, DK 20495)
- National Institute on Drug Abuse (PL1DA024859, T32DA022975)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK20495, R01DK020495, R37DK020495, T32DK007058, P30DK045735)
- National Institute of Dental and Craniofacial Research (UL1DE019586)
- National Center for Research Resources (UL1RR024139)
- Yale Center for Clinical Investigation, Yale School of Medicine (UL1RR024139)
- Common Fund (PL1-DA024859, UL1-DE019586)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Social Sciences › Psychology › Clinical Psychology › Eating Disorders and Behaviors
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- circulating glucose, hypoglycemia, food motivation, high-calorie foods, obesity, medial prefrontal cortex, food cues, hyperinsulinemic-euglycemic clamp, overeating, postprandial blood glucose
- MeSH terms
- Adult, Appetite, Appetite Regulation, Blood Glucose, Brain, Energy Intake, Feeding Behavior, Female, Humans, Hunger, Hypoglycemia, Magnetic Resonance Imaging, Male, Neurosecretory Systems, Obesity, Photic Stimulation, Glucose Clamp Technique, Prefrontal Cortex, Young Adult
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