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.

Figures

Figure 1. Study procedure.

(A) While subjects were in the scanner, a hyperinsulinemic clamp was performed with a constant infusion of insulin along with variable amounts of glucose to maintain euglycemic conditions for the first 60 minutes. For the stepped clamp study (n = 14), plasma glucose was then lowered to approximately 65 mg/dl for the hypoglycemic phase. For the euglycemic control study (n = 7), plasma glucose was maintained at approximately 90 mg/dl (dotted line). During both conditions, functional scans were performed while subjects viewed images that were projected onto a screen in the scanner. (B) Time course of a single trial. Each trial consisted of 3 events. First, a high-calorie food, low-calorie food, or non-food picture appeared for 6 seconds. Second, two rating scales were presented for 3 seconds each and consisted of liking and wanting scales with values 1–9, where a rating of 1 indicated “not at all” and a rating of 9 indicated “very much.” At the end of a trial, a fixation cross appeared, and subjects relaxed until the onset of the next trial.

Figure 2. Plasma glucose and insulin levels.

(A) Plasma glucose and (B) insulin levels (mean ± SEM) during the stepped euglycemic-hypoglycemic (black circles) and euglycemic control (white squares) study sessions. *P < 0.001 unpaired t test, euglycemic versus hypoglycemic session.

Figure 3. Differences between euglycemic and hypoglycemic conditions.

Axial slices with (A) whole group, covaried for BMI (n = 14), (B) obese group (n = 5), and (C) nonobese group (n = 9) averages, showing brain response to euglycemia compared with mild hypoglycemia across visual cue tasks (threshold of P < 0.05, 2 tailed, FWE whole brain corrected). Red and yellow areas show greater activity during euglycemia, and blue areas indicate greater activity during hypoglycemia. The color scale gives the t value of the functional activity. Eu, euglycemia; Hypo, hypoglycemia; NAcc, nucleus accumbens; Hyp, hypothalamus; VMPFC, ventromedial prefrontal cortex; Hipp, hippocampus; L, left; R, right. MNI coordinates were used to define brain regions.

Figure 4. Condition × task effects.

(A) Axial slices with group averages (n = 14), covaried for BMI, showing brain response to food (high-calorie and low-calorie) cues under euglycemia compared with mild hypoglycemia (threshold of P < 0.05, 2-tailed, FWE whole brain corrected). (B) Wanting and liking ratings for food during euglycemia (gray bars) and mild hypoglycemia (black bars). *P = 0.02. (C) Brain response specifically to high-calorie food images under euglycemia compared with mild hypoglycemia (threshold of P < 0.05, 2-tailed, FWE whole brain corrected). (D) Wanting and liking ratings for high-calorie foods during euglycemia (gray bars) and mild hypoglycemia (black bars); **P = 0.006. Red/orange areas show greater activity, and blue areas indicate more suppressed activity during euglycemia relative to hypoglycemia. MNI coordinates were used to define brain regions.

Figure 5. Whole-brain, voxel-based correlation analyses.

Axial brain slices and corresponding scatter plots showing correlations between (A) plasma glucose levels and VMPFC/ACC response to high-calorie food images; and (B) plasma cortisol levels and left and right insula/striatal response to high-calorie food images. P < 0.01, 2-tailed, FWE whole brain corrected. Areas in yellow indicate brain regions positively correlated to plasma glucose and plasma cortisol levels. There were no outliers in these associations. MNI coordinates were used to define brain regions.