Stokes et al. demonstrate that PARP7 “senses” the levels of nuclear NAD+ during early adipogenic differentiation via an ADP-ribosylation-ubiquitin-proteasome pathway to regulate C/EBPβ-dependent proadipogenic gene expression through p300-mediated H3K27 acetylation. Stabilized PARP7 promotes the binding of C/EBPβ to chromatin genome-wide, enhancing lipid synthesis and adipogenesis in vivo.