A systemic circadian nicotinic acid riboside (NaR) signal engages the unfolded protein response and adipogenesis via the prefoldin complex

Abstract Daily light–dark cycles impose predictable environmental fluctuations that require coordinated temporal regulation of cellular physiology. This coordination is mediated by the circadian clock, which operates as a network of tissue oscillators; however, the molecular signals that convey circadian information between organs remain incompletely defined. Here, we identify nicotinic acid riboside (NaR) as a circulating metabolite whose rhythmicity depends on the liver clock. In differentiating 3T3-L1 adipocytes, NaR engages unfolded protein response (UPR) gene programs and modulates adipogenic competence. Proteome-wide stability profiling implicates the prefoldin complex as a molecular target of NaR signaling, linking NaR exposure to altered proteostasis. Functionally, NaR-induced UPR signaling converges on the adipogenic transcription factor CEBPA, which is a central regulator of adipogenesis. Importantly, sustained NaR exposure suppresses adipocyte lipid deposition, whereas temporally restricted NaR stimulation enhances adipogenesis, indicating that NaR acts in a time-dependent manner. Together, these findings identify NaR as a liver clock–controlled circulating metabolite that couples systemic circadian metabolism to adipocyte proteostasis and differentiation, revealing a mechanism by which temporal metabolic signals shape tissue-specific physiological outcomes. Highlights The circadian clock is required for rhythmic regulation of circulating nicotinic acid riboside (NaR). The liver clock is sufficient to generate NaR rhythmicity. NaR engages the prefoldin complex to regulate unfolded protein response signaling and Cebpa expression. Time-dependent NaR exposure differentially regulates CEBPA levels and adipocyte lipid deposition. Competing Interest Statement The authors have declared no competing interest.