Cellular differentiation involves dynamic epigenetic, transcriptional, and metabolic remodeling as cells transition to a new identity. Evidence is mounting that metabolism and gene regulation are intimately linked, with changes in metabolite availability modulating or even triggering gene transcription. One way that metabolites regulate gene expression is as substrates of enzymes that carry out posttranslational modification of transcription factors and histones. Such metabolites likely have distinct biological roles in different compartments of the cell, and in particular within the nucleus (1, 2). Yet, the extent to which the nucleus is a separate metabolic compartment from the cytosol and the mechanisms by which nuclear metabolite levels affect expression of specific genes have remained largely unknown. On page 618 of this issue, Ryu et al. (3) demonstrate that compartmentalized synthesis of the metabolite oxidized nicotinamide adenine dinucleotide (NAD⁺), regulates adipocyte differentiation, a process that is essential for metabolic health, through transcriptional control.