Coordination between metabolic transitions and gene expression by NAD+ availability during adipogenic differentiation in human cells.
Adipocytes are the main cell type in adipose tissue, a critical regulator of metabolism, highly specialized in storing energy as fat. Adipocytes differentiate from multipotent mesenchymal stromal cells through adipogenesis, a tightly controlled differentiation process involving closely interplay between metabolic transitions and sequential programs of gene expression. However, the specific gears driving this interplay remain largely obscure. Additionally, the metabolite nicotinamide adenine dinucleotide (NAD+) is becoming increasingly recognized as a regulator of lipid metabolism, being postulated as promising therapeutic target for dyslipidemia and obesity. Here, we explored the effect of manipulating NAD+ bioavailability during adipogenic differentiation from human mesenchymal stem cells. We found a previously unappreciated strong repressive role for NAD+ on adipocyte commitment, while a functional NAD+-dependent deacetylase SIRT1 appeared crucial for terminal differentiation of pre-adipocytes. Remarkably, repressing the NAD+ biosynthetic salvage pathway during adipogenesis promoted the adipogenic transcriptional program, suggesting that SIRT1 activity during adipogenesis is independent from the NAD+ salvage pathway, while two photon microscopy and extracellular flux analyses suggest that its activation relies on the metabolic switch. Interestingly, SIRT1-directed control of subcellular compartmentalization of redox metabolism during adipogenesis was evidenced by two-photon fluorescence lifetime microscopy.