Brain insulin sensitivity is linked to adiposity and body fat distribution

Abstract

Brain insulin action regulates eating behavior and energy fluxes throughout the body. However, numerous people are brain insulin resistant. How brain insulin responsiveness affects long-term weight and body fat composition in humans is still unknown. Here we show that high brain insulin sensitivity before lifestyle intervention associates with a more pronounced reduction in total and visceral fat during the program. High brain insulin sensitivity is also associated with less regain of fat mass during a nine year follow-up. Cross-sectionally, strong insulin responsiveness of the hypothalamus associates with less visceral fat, while subcutaneous fat is unrelated. Our results demonstrate that high brain insulin sensitivity is linked to weight loss during lifestyle intervention and associates with a favorable body fat distribution. Since visceral fat is strongly linked to diabetes, cardiovascular risk and cancer, these findings have implications beyond metabolic diseases and indicate the necessity of strategies to resolve brain insulin resistance.

Fig. 1. Body composition during/after 9 years of lifestyle intervention depending on brain insulin sensitivity.

(a) Changes in body weight; (b) changes in visceral adipose tissue (VAT); (c) changes in subcutaneous adipose tissue (SCAT). Brain insulin sensitivity was assessed as change in the theta frequency band in response to insulin infusion, corrected for saline infusion by magnetoencephalography. p values are from MANOVAs with brain insulin responsiveness as a continuous variable (brain insulin sensitivity × time). N = 15 (a), N = 12 (b, c); presented are means, error bars represent SEM. Filled boxes represent participants with brain insulin responsiveness below the median, open circles represent participants with brain responsiveness above the median. Continuous variables were used for statistical analyses and stratified variables were used solely for better illustration of the results. Source data are provided as a Source Data file.

Fig. 2. Hypothalamic insulin responsiveness associates with body fat distribution.

Region-specific change in cerebral blood flow in response to intranasal insulin administration was extracted for the hypothalamus as region of interest (a). Participants with a strong insulin-induced suppression in hypothalamic blood flow had significantly less visceral adipose tissue (b). Subcutaneous fat content was not associated with insulin sensitivity of the hypothalamus (c). The ratio of visceral to subcutaneous adipose tissue was favorably lower in those with strong insulin-induced hypothalamic blood flow (d). Pink filled circles are female participants (N = 53), open blue circles are males (N = 59). Lines represent fit lines ±CI. p values are from unadjusted linear regression models. Source data are provided as a Source Data file.