Elevated microRNA‐34a in obesity reduces NAD+ levels and SIRT1 activity by directly targeting NAMPT

Summary SIRT1 is an NAD + ‐dependent deacetylase that is implicated in prevention of many age‐related diseases including metabolic disorders. As SIRT1 deacetylase activity is dependent on NAD + levels and the development of compounds that directly activate SIRT1 has been controversial, indirectly activating SIRT1 through enhancing NAD + bioavailability has received increasing attention. NAD + levels are reduced in obesity and the aged, but the underlying mechanisms remain unclear. We recently showed that hepatic microRNA‐34a (miR‐34a), which is elevated in obesity, directly targets and decreases SIRT1 expression. Here, we further show that miR‐34a reduces NAD + levels and SIRT1 activity by targeting NAMPT, the rate‐limiting enzyme for NAD + biosynthesis. A functional binding site for miR‐34a is present in the 3′ UTR of NAMPT mRNA . Hepatic overexpression of miR‐34a reduced NAMPT/NAD + levels, increased acetylation of the SIRT1 target transcriptional regulators, PGC‐1α, SREBP‐1c, FXR, and NF‐κB, and resulted in obesity‐mimetic outcomes. The decreased NAMPT/NAD + levels were independent of miR‐34a effects on SIRT1 levels as they were also observed in SIRT1 liver‐specific knockout mice. Further, the miR‐34a‐mediated decreases were reversed by treatment with the NAD + intermediate, nicotinamide mononucleotide. Conversely, antagonism of miR‐34a in diet‐induced obese mice restored NAMPT/NAD + levels and alleviated steatosis, inflammation, and glucose intolerance. Anti‐miR‐34a‐mediated increases in NAD + levels were attenuated when NAMPT was downregulated. Our findings reveal a novel function of miR‐34a in reducing both SIRT1 expression and activity in obesity. The miR‐34a/NAMPT axis presents a potential target for treating obesity‐ and aging‐related diseases involving SIRT1 dysfunction like steatosis and type 2 diabetes.