Insights to the neural response to food cues in class III compared with class I and II obese adults using a sample of endometrial cancer survivors seeking weight loss

Severe (Class III) obesity (BMI ≥ 40 kg/m²) has risen markedly in the U.S. and is associated with substantial reductions in life expectancy. Endometrial cancer (EC), largely comprising endometrial (uterine) cancers, has concurrently increased in incidence and mortality; obesity is a strong risk factor for EC development and death. Obesity involves complex biological and behavioral mechanisms, including altered neural reward processing that may promote overconsumption of high-calorie foods. Prior neuroimaging studies in non-cancer populations with obesity indicate heightened activation to high-calorie food cues in reward, taste, attention, motivation, and memory regions; data specific to severely obese adults and comparisons across obesity classes are limited, often confounded by post-bariatric surgery changes. A prior pilot study in EC survivors with obesity showed increased activation to high-calorie cues in frontal regions, but sample size precluded stratification by obesity class. This study aimed to evaluate neural responses to visual food cues by obesity class (Class I/II vs. Class III) among obese EC survivors seeking weight loss at baseline. The hypothesis was that Class III obese women would exhibit greater activation in food reward and motivation regions in response to high-calorie versus non-food images, persisting after a meal.

The paper reviews evidence linking obesity to enhanced neural reactivity to high-calorie food cues, including increased activation in dorsal striatum (reward anticipation), anterior insula and lateral orbitofrontal cortex (taste processing and motivation), posterior cingulate (memory), anterior cingulate (attention), precentral gyrus and cerebellum (motor processes), and broader reward circuitry (striatum, amygdala, OFC). Studies in severely obese adults are limited and often post-bariatric, showing altered hypothalamic and mesolimbic responses and reduced dorsolateral frontal activation post-surgery. In EC survivors with obesity (prior pilot), increased DLPFC and OFC activation to high-calorie cues was observed pre-meal; post-meal increases were seen in thalamus, posterior cingulate, and precuneus. Meta-analyses suggest moderate concordance across visual food cue neuroimaging studies and overlap with cue-reactivity to drugs, implicating DLPFC, precuneus, and medial frontal regions. The existing literature lacks comparisons across obesity classes, motivating the current study.

Design and participants: Cross-sectional baseline neuroimaging within a randomized lifestyle intervention cohort. Participants were 85 Stage I endometrial cancer survivors with obesity (BMI ≥ 30 kg/m²) enrolled at University Hospitals Case Medical Center and the Cleveland Clinic (ClinicalTrials.gov NCT01870947). All provided written informed consent; IRB approvals were obtained. Procedures: Participants fasted overnight and underwent structural and functional MRI scanning between ~11:00 a.m. and 1:00 p.m. A standardized 1000 kcal luncheon meal was provided; participants ate to satiation, with leftovers weighed to quantify intake. Approximately 25–30 minutes after the first scan (fasted), a second fMRI session was conducted (fed). Behavioral measures: Pre-scan, participants rated liking for 74 food items (high- and low-calorie) on a 5-point Likert scale. Immediately before each scan, hunger was rated on a visual analog scale. Task: Visual food cue blocked perceptual discrimination task. Participants indicated via button press whether side-by-side images (same category per block: high-calorie foods, low-calorie foods, non-food objects) were the same or different. Two runs per session; each run had eight 21 s blocks (six image pairs/block) with 14 s rest intervals. Stimulus duration 2250 ms; 1250 ms inter-stimulus interval. Block order was counterbalanced. MRI acquisition: Siemens 3.0T Verio/Skyra, 12-channel head coil. Functional BOLD EPI: 34 axial slices aligned to AC-PC; in-plane 3.4×3.4×3 mm; TR=1950 ms, TE=22 ms, flip=90°, two runs of 5:01 min (157 volumes). 2D T1 (TR=300 ms, TE=2.47 ms, FOV=256, 256×256, flip=60°, NEX=2) for registration, and 3D MPRAGE (1 mm isotropic; TR=2500 ms, TE=3.52 ms, TI=1100 ms, FOV=256, 256×256, flip=12°, NEX=1) for normalization. Preprocessing and analysis: BrainVoyager 20.2. Steps: trilinear 3D motion correction; 2D Gaussian spatial smoothing (FWHM 7 mm); high-pass temporal filtering/linear trend removal; alignment to 3D anatomy; Talairach normalization; resampling to 3 mm³ voxels. Motion parameters included in design; volumes with >2 mm displacement discarded (<1%). Random-effects GLM assessed contrasts of high-calorie vs. non-food separately for pre-meal (fasted) and post-meal (fed). Multiple comparisons controlled via whole-brain cluster-based thresholding (Cluster Thresh plugin) using 1000 Monte Carlo simulations; initial uncorrected p<0.001–0.005; minimum cluster size 10–68 voxels (260–798 mm³) to achieve family-wise error p<0.05. Secondary analyses: For significant clusters, mean β-values were extracted per participant. One-way ANOVAs compared Class III vs. Class I/II groups for effect magnitudes. Correlations were explored between β-values in significant regions and food liking scores, as well as meal intake (total energy, macronutrients).

- Sample characteristics: n=85; mean age ~60 years; 91.8% Caucasian; 45% Class I/II (n=38), 55% Class III (n=47); mean BMI 41.8±8.2 kg/m². Hunger decreased post-meal similarly across groups. - Food preferences and intake: High-calorie liking higher in Class III vs. Class I/II (4.08±0.46 vs. 3.86±0.46; p=0.04). Class III consumed more total energy (584.0±173.9 vs. 506.5±142.5 kcal; p=0.03), fat (27.5±10.0 vs. 23.5±8.2 g; p<0.05), and protein (38.6±13.4 vs. 31.6±9.5 g; p<0.01). - Whole sample neural responses: • Fasted: Increased activation to high-calorie vs. non-food in OFC (BA47) and DLPFC (BA46) (WBCC p<0.05). • Fed: Increased activation in precuneus (BA39), DLPFC (BA46), and MFG (BA6); decreased activation in posterior cingulate (BA30), fusiform gyrus (BA37), and putamen. - By obesity class: • Class I/II fasted: No significant increased activations after cluster correction; decreased activation in insula (BA13), parahippocampal gyrus (BA36), and posterior cingulate (BA30). • Class I/II fed: Increased activation in DLPFC (BA46); decreased activation in parahippocampal gyrus (BA36). • Class III fasted: Increased activation in OFC (BA47), DLPFC (BA46), precuneus (BA31), parahippocampal gyrus (BA34, bilateral), and precentral gyrus (BA6). • Class III fed: Increased activation in DLPFC (BA46, bilateral) and precuneus (BA7, bilateral); decreased activation in caudate and posterior cingulate (BA30). - Between-group differences (fasted): DLPFC activation higher in Class III vs. Class I/II (β 0.11±0.03 vs. 0.02±0.04; p=0.04). Insula activation lower in Class I/II vs. Class III (β -0.09±0.03 vs. -0.01±0.02; p=0.03). OFC activation trended higher in Class III (β 0.13±0.04 vs. 0.03±0.05; p=0.09). No significant between-group differences post-meal. - Correlations: Post-meal DLPFC activation positively correlated with carbohydrate intake in both groups (Class III r=0.32, p=0.03; Class I/II r=0.33, p<0.05). In Class III, post-meal DLPFC activation inversely correlated with fat intake (r=-0.29, p=0.04) and fruit/vegetable liking (r=-0.29, p<0.05). No significant correlations between DLPFC or insula activation and high-calorie liking or total energy, protein, fat (except as above).

The study demonstrates that both Class I/II and Class III obese EC survivors show increased DLPFC activation to high-calorie versus non-food cues, with significantly greater DLPFC activation in Class III in the fasted state. This supports the hypothesis that obesity severity is associated with heightened engagement of cognitive control/inhibitory regions during exposure to high-calorie cues. The persistence of DLPFC activation post-meal across classes suggests sustained attentional/inhibitory processing of food cues even in a satiated state. Unexpectedly, Class I/II exhibited decreased insula activation (taste processing) in the fasted state relative to Class III, diverging from some prior reports and indicating potential class-specific alterations in gustatory/interoceptive processing. In Class III, additional fasted-state increases in precuneus and precentral gyrus suggest enhanced attentional bias and motor preparatory processes toward food cues. Post-meal DLPFC activation correlated with higher carbohydrate intake in both classes and with lower fat intake and lower fruit/vegetable liking in Class III, implying that sustained cognitive control/attention to high-calorie cues may relate to macronutrient selection and lower preference for healthier options. Collectively, these findings align with literature showing DLPFC involvement in eating restraint and cue-reactivity overlaps with addiction-related circuitry (DLPFC, precuneus, MFG). The observed insula decrease, particularly in Class I/II, warrants further investigation and may reflect sample characteristics (older, cancer survivors) or methodological differences compared to prior studies of younger, non-cancer populations. These results highlight potential targets for behavioral and neuromodulatory interventions—especially enhancing inhibitory control via DLPFC-focused strategies—for weight management, with possibly greater relevance for severely obese individuals.

This study provides the first comparative assessment of neural responses to visual food cues across obesity classes in obese endometrial cancer survivors. Key contributions include: (1) greater fasted-state DLPFC activation in Class III vs. Class I/II obesity and persistent DLPFC engagement post-meal across classes; (2) unexpected fasted-state insula hypoactivation more pronounced in Class I/II; and (3) associations between post-meal DLPFC activation and macronutrient intake and food preferences. These findings suggest that interventions targeting DLPFC-mediated cognitive control (e.g., attention training, transcranial direct current stimulation) may be beneficial for weight loss, particularly in Class III obesity. Future research should replicate these findings in larger, diverse cohorts, include non-cancer controls, examine causal mechanisms, and test DLPFC-targeted interventions’ effects on eating behavior and weight outcomes across obesity classes.

- No non-cancer obese control group and no normal-weight controls for direct comparison. - First study to examine neural food cue responses by obesity class; limited ability to assess consistency with prior literature. - Sample comprised older female EC survivors; findings may not generalize to younger or non-cancer populations. - Neuroimaging reproducibility concerns: differences in task designs, stimuli, hunger states, and analytic thresholds may affect comparability. - Cross-sectional baseline analyses prevent causal inference; correlational findings between activation and intake/preferences are exploratory. - Potential scanner/site and equipment variations (Verio vs. Skyra) not explicitly modeled beyond standard preprocessing.