Significance : Nutrition and the body clock are deeply intertwined, both impinging on our physiological health. Food composition can dramatically rewire peripheral clock metabolism; however, whether food challenges can impact circadian metabolism of the master clock in the suprachiasmatic nucleus (SCN) or other brain areas has not been fully explored. Here we analyzed the complete diurnal metabolome of the SCN and medial prefrontal cortex (mPFC) in mice fed a balanced diet or a high-fat diet (HFD). Strikingly, our data reveal unexpected daily rhythmicity in both SCN and mPFC metabolites that is significantly impacted by HFD in a region-specific manner. Our findings unveil an unsuspected sensitivity of brain clocks to nutrition. Abstract : Food is a powerful entrainment cue for circadian clocks in peripheral tissues, and changes in the composition of nutrients have been demonstrated to metabolically reprogram peripheral clocks. However, how food challenges may influence circadian metabolism of the master clock in the suprachiasmatic nucleus (SCN) or in other brain areas is poorly understood. Using high-throughput metabolomics, we studied the circadian metabolome profiles of the SCN and medial prefrontal cortex (mPFC) in lean mice compared with mice challenged with a high-fat diet (HFD). Both the mPFC and the SCN displayed a robust cyclic metabolism, with a strikingly high sensitivity to HFD perturbation in an area-specific manner. The phase and amplitude of oscillations were drastically different between the SCN and mPFC, and the metabolic pathways impacted by HFD were remarkably region-dependent. Furthermore, HFD induced a significant increase in the number of cycling metabolites exclusively in the SCN, revealing an unsuspected susceptibility of the master clock to food stress.