Animal studies suggest that obesity-related diets induce structural changes in the
hypothalamus, a key brain area involved in energy homeostasis. Whether this translates
to humans is however largely unknown. Using a novel multimodal approach with manual
segmentation, we here show that a higher body mass index (BMI) selectively predicted
higher proton diffusivity within the hypothalamus, indicative of compromised microstructure
in the underlying tissue, in a well-characterized population-based cohort (n(1) =
338, 48% females, age 21-78 years, BMI 18-43 kg/m(2)). Results were independent from
confounders and confirmed in another independent sample (n(2) = 236). In addition,
while hypothalamic volume was not associated with obesity, we identified a sexual
dimorphism and larger hypothalamic volumes in the left compared to the right hemisphere.
Using two large samples of the general population, we showed that a higher BMI specifically
relates to altered microstructure in the hypothalamus, independent from confounders
such as age, sex and obesity-associated co-morbidities. This points to persisting
microstructural changes in a key regulatory area of energy homeostasis occurring with
excessive weight. Our findings may help to better understand the pathomechanisms of
obesity and other eating-related disorders.