A short-term, high-caloric diet has prolonged effects on brain insulin action in men

Abstract

Brain insulin responsiveness is linked to long-term weight gain and unhealthy body fat distribution. Here we show that short-term overeating with calorie-rich sweet and fatty foods triggers liver fat accumulation and disrupted brain insulin action that outlasted the time-frame of its consumption in healthy weight men. Hence, brain response to insulin can adapt to short-term changes in diet before weight gain and may facilitate the development of obesity and associated diseases.

Fig. 1. Schematic overview of the study design.

After initial screening, healthy weight male participants underwent two baseline assessment days after an overnight fast at ~08:00. On the brain MRI testing day, diffusion-weighted imaging and CBF responses to 160 IU INI were acquired to investigate white matter integrity and brain insulin action (∆CBF = CBF MRI-2 − CBF MRI-1), respectively, followed by a reward-learning task. On a separate testing day (1–3 days apart), whole-body MRI for measurement of body fat mass and distribution and oGTTs for measurement of peripheral insulin sensitivity were performed. Afterwards, 18 participants were instructed to increase their daily caloric intake by 1,500 kcal for five consecutive days with high-caloric snacks. Eleven participants maintained their regular diet. Both testing days were repeated immediately after the 5-day HCD or regular diet period at follow-up 1. At follow-up 2, the brain MRI testing day was repeated 7 days after resuming a regular diet. Eating behaviour questionnaires were acquired during all testing days. Between visits, participants recorded their food intake and daily step activity. The timing of the follow-up visits was adapted to the first day of the HCD recording. Figure created in BioRender.

Fig. 2. Disrupted brain insulin action after short-term overeating with calorie-rich snacks.

a, Changes in brain insulin activity at follow-up 1 (directly after the 5-day HCD or regular diet) and follow-up 2 (1 week after resuming the regular diet) in HCD compared with the control group. Regions with significant changes in CBF after INI application in the HCD group compared with the control group and adjusted for the baseline measurement day are shown. Colour maps correspond to t-values (P < 0.001, uncorrected for display). b, Areas in the brain showing significantly higher insulin activity at follow-up 1 in the HCD compared with the control group adjusted for baseline measurement (P_FWE < 0.05, whole-brain cluster level corrected). n = 29 at baseline and follow-up 1. c, Areas in the brain showing significantly lower insulin activity at follow-up 2 in the HCD compared with the control group adjusted for baseline measurement day (P_FWE < 0.05, whole-brain cluster level corrected). n = 29 at baseline, n = 28 at follow-up 2. Box plots show at the centre the median values indicated by thick horizontal lines; upper and lower hinges correspond to first and third quartiles (25th and 75th percentiles). The whiskers extend from the hinges to the minimum and maximum value, which is 1.5 × interquartile range of the hinge. d, Higher brain insulin responsiveness at follow-up 1 (adjusted for the baseline visit) significantly correlated with the fold change in liver fat (n = 28; r = 0.434, P = 0.02), the food diary reported fold change in saturated fatty acid (SFA) intake (n = 29; r = 0.531, P = 0.003) and the change in reward sensitivity (n = 29) (r = −0.460, P = 0.01) at follow-up 1 adjusted for baseline. Source data

Extended Data Fig. 1. Liver fat content in the control and high-caloric diet group (HCD) at baseline and 5-days after the high-caloric or regular diet intervention (follow-up 1).

Liver fat content increased in the HCD group: baseline versus follow-up 1: p = 0.005, while it did not change in the control group (p = 0.958). Presented are box plots with whiskers indicating 1.5 interquartile range and line diagram; Control: N = 11 at baseline and follow-up 1; HCD: N = 17 at baseline and N = 18 follow-up 1. Abbreviations: HCD, high-caloric diet group. Source data

Extended Data Fig. 2. HCD reduced reward sensitivity and increased punishment sensitivity.

Bootstrapped density plots of the difference between groups in changes of parameter estimates at follow-up 1 and follow-up 2 compared to baseline (pre), respectively. Lines indicate 95% confidence intervals. HCD = high-caloric diet group; RewS = Reward Sensitivity, Pav = Pavlovian, LL = log-likelihood. Source data

Extended Data Fig. 3. Change in white matter organization at follow-up 2.

Change in white matter organization at follow-up 2 in the high-caloric diet compared to the control group. The panel shows the fractional anisotropy skeleton (in green) representing the major white matter tracts of all participants overlayed on a MNI standard brain. White matter fibre tracts showing a significantly lower fractional anisotropy (FA) at follow-up 2 in the high-caloric diet compared to the control group are shown in red, orange and yellow (p-corr <0.05). Lower FA values are mainly located on inferior fronto-occipital fasciculus, genu of the corpus callosum and anterior corona radiata (white circles). Colorbar represents 1-p value (tfce-corrected). Tracts in yellow displayed smaller p value or more significant results. N = 27. Source data