The human brain undergoes metabolic adaptations in obesity, but the underlying mechanisms have remained largely unknown. We compared concentrations of often reported brain metabolites measured with magnetic resonance spectroscopy (¹H-MRS, 3 T MRI) in the occipital lobe in subjects with obesity and lean controls under different metabolic conditions (fasting, insulin clamp, following weight loss). Brain glucose uptake (BGU) quantified with ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG-PET)) was also performed in a subset of subjects during clamp. In dataset A, 48 participants were studied during fasting with brain ¹H-MRS, while in dataset B 21 participants underwent paired brain ¹H-MRS acquisitions under fasting and clamp conditions. In dataset C 16 subjects underwent brain ¹⁸F-FDG-PET and ¹H-MRS during clamp. In the fasting state, total N-acetylaspartate was lower in subjects with obesity, while brain
myo-inositol increased in response to hyperinsulinemia similarly in both lean participants and subjects with obesity. During clamp, BGU correlated positively with brain glutamine/glutamate, total choline, and total creatine levels. Following weight loss, brain creatine levels were increased, whereas increases in other metabolites remained not significant. To conclude, insulin signaling and glucose metabolism are significantly coupled with several of the changesin brain metabolites that occur in obesity.