Dopamine D2 receptor signaling in the brain modulates circadian liver metabolomic profiles

The circadian clock is tightly intertwined with metabolism and relies heavily on multifaceted interactions between organ systems to maintain proper timing. Genetic and/or environmental causes can disrupt communication between organs and alter rhythmic activities. Substance use leads to altered dopamine signaling followed by reprogramming of circadian gene expression and metabolism in the reward system. However, whether altered dopamine signaling in the brain affects circadian metabolism in peripheral organs has not been fully explored. We show that dopamine D2 receptors (D2R) in striatal medium spiny neurons (MSNs) play a key role in regulating diurnal liver metabolic activities. In addition, drugs that increase dopamine levels, such as cocaine, disrupt circadian metabolic profiles in the liver, which is exacerbated by loss of D2R signaling in MSNs. These results uncover a strict communication between neurons/brain areas and liver metabolism as well as the association between substance use and systemic deficits.