Time-of-day defines the efficacy of NAD+ to treat diet-induced metabolic disease by adjusting oscillations of the hepatic circadian clock

The circadian clock is a time-tracking endogenous system which anticipates and coordinates adaptation to daily environmental fluctuations. Circadian misalignment leads to obesity, which is accompanied by reduced levels of the clock-controlled metabolite NAD+. Concomitantly, increasing NAD+ levels is emerging as a therapy for diet-induced obesity and type 2 diabetes; however, the impact of daily fluctuations of NAD+ on these therapies remains unknown. Here, we demonstrate that time-of-day determines the efficacy of NAD+ as a therapy for diet-induced metabolic disease in mice. Restoring regular NAD+ oscillations at the onset of the active phase ameliorates metabolic markers of disease such as body weight and glucose and insulin tolerance, and restores hepatic gene expression related to inflammatory response and lipid metabolism. However, the same treatment designed to increase NAD+ at the onset of the rest phase severely compromises these beneficial responses. Notably, hepatic nutrient-sensing mTOR, AMPK or AKT signaling, became rhythmic specifically in obese mice treated just before the active phase. Remarkably, NAD+ at the onset of the rest phase was accompanied by uncoupled oscillations between the SCN and the hepatic clock, which were phase inverted in the liver, while keeping behavioral rhythms largely intact. These findings demonstrate that the time of day determines the beneficial effects of NAD+-based therapies and pave the way for the basic strategy of a chronobiology-based therapeutic approach.