Metabolic regulation of transcription through compartmentalized NAD⁺ biosynthesis

NAD⁺ (nicotinamide adenine dinucleotide in its oxidized state) is an essential molecule for a variety of physiological processes. It is synthesized in distinct subcellular compartments by three different synthases (NMNAT-1, -2, and -3). We found that compartmentalized NAD⁺ synthesis by NMNATs integrates glucose metabolism and adipogenic transcription during adipocyte differentiation. Adipogenic signaling rapidly induces cytoplasmic NMNAT-2, which competes with nuclear NMNAT-1 for the common substrate, nicotinamide mononucleotide, leading to a precipitous reduction in nuclear NAD⁺ levels. This inhibits the catalytic activity of poly[adenosine diphosphate (ADP)-ribose] polymerase-1 (PARP-1), a NAD⁺-dependent enzyme that represses adipogenic transcription by ADP-ribosylating the adipogenic transcription factor C/EBPβ. Reversal of PARP-1-mediated repression by NMNAT-2-mediated nuclear NAD⁺ depletion in response to adipogenic signals drives adipogenesis. Thus, compartmentalized NAD⁺ synthesis functions as an integrator of cellular metabolism and signal-dependent transcriptional programs.