Obesity Is Associated With Low NAD⁺/SIRT Pathway Expression in Adipose Tissue of BMI-Discordant Monozygotic Twins

CONTEXT: Sirtuins (SIRTs) regulate cellular metabolism and mitochondrial function according to the energy state of the cell reflected by NAD(+) levels. OBJECTIVE: Our aim was to determine whether expressions of SIRTs and NAD(+) biosynthesis genes are affected by acquired obesity and how possible alterations are connected with metabolic dysfunction while controlling for genetic and familial factors. DESIGN AND PARTICIPANTS: We studied a cross-sectional sample of 40 healthy pairs of monozygotic twins, including 26 pairs who were discordant for body mass index (within-pair difference > 3 kg/m(2)), from the FinnTwin12 and FinnTwin16 cohorts. MAIN OUTCOME MEASURES: Subcutaneous adipose tissue (SAT) transcriptomics was analyzed by using Affymetrix U133 Plus 2.0 chips, total SAT (poly-ADP) ribose polymerase (PARP) activity by an ELISA kit, body composition by dual-energy x-ray absorptiometry and magnetic resonance imaging/spectroscopy, and insulin sensitivity by an oral glucose tolerance test. RESULTS: SIRT1, SIRT3, SIRT5, NAMPT, NMNAT2, NMNAT3, and NRK1 expressions were significantly down-regulated and the activity of main cellular NAD(+) consumers, PARPs, trended to be higher in the SAT of heavier co-twins of body mass index-discordant pairs. Controlling for twin-shared factors, SIRT1, SIRT3, NAMPT, NMNAT3, and NRK1 were significantly negatively correlated with adiposity, SIRT1, SIRT5, NMNAT2, NMNAT3, and NRK1 were negatively correlated with inflammation, and SIRT1 and SIRT5 were positively correlated with insulin sensitivity. Expressions of genes involved in mitochondrial unfolded protein response were also significantly down-regulated in the heavier co-twins. CONCLUSIONS: Our data highlight a strong relationship of reduced NAD(+)/SIRT pathway expression with acquired obesity, inflammation, insulin resistance, and impaired mitochondrial protein homeostasis in SAT.