Targeting mitochondrial function is a strategy for preventing metabolic disorders, but restoring mitochondria diurnal regulation remains to be explored. Using targeted metabolomics, we identified 24-hour mitochondrial rhythms promoted by nocturnal time-restricted feeding (TRF) in mice fed a high-fat diet (HFD). Preceding its metabolic benefits, TRF promoted mitochondrial daily rhythms by converging on the enzyme dihydroorotate dehydrogenase (DHODH), which coordinates pyrimidine biosynthesis and mitochondrial oxidative metabolism. The inhibition of DHODH activity by the short half-life inhibitor BAY-2402234 modulated mitochondrial oxidative metabolism, thereby preventing diet-induced obesity, but only when injected at the transition between night and day. This timed inhibition of DHODH
promoted oscillations in mitochondrial metabolic pathways and oscillations in the CoQ/CoQH2 ratio, improving metabolic adaptation to the HFD challenge. Our results highlight the role of mitochondrial daily rhythms in the pathophysiology of obesity and open avenues for chronopharmacological treatments targeting these rhythms.
Thus, the present invention pertains to a method for treating or preventing obesity in a subject in need thereof. This method includes administering to the subject, at a specific time of the circadian rhythm, a therapeutically effective amount of a dihydroorotate dehydrogenase inhibitor that exhibits an inhibitory duration of less than 24 hours, and more specifically, a short half-life of less than 24 hours.