NAD+ repletion attenuates obesity‐induced oocyte mitochondrial dysfunction and offspring metabolic abnormalities via a SIRT3‐dependent pathway

Dear Editor, Over-nutrition in females causes subfertility and impairs offspring health, but the detail mechanisms and therapeutic strategies has not been well investigated.1–3 Nicotinamide adenine dinucleotide (NAD) is an important cofactor that regulates mitochondrial functions.4–6 In this study, we revealed that obesity induced NAD decline in oocyte, while supplementation of NAD precursor, nicotinamide riboside (NR), in HFD-fed mice alleviated subfertility and reduced metabolic dysfunction in offspring through a NAD-SIRT3-dependent pathway. An obese mouse model was established by feeding female mice a high-fat diet (HFD) supplemented with or without NR (400 mg/kg/day) for 3 months beginning at the age of 4 weeks (Figure S1). The NAD levels in ovaries and MII oocytes from HFD mice decreased dramatically in comparison with controls. RT-PCR results showed that the key rate-limited NAD biosynthesis gene Nampt was marked decreased in the obese oocytes (Figure S4A). However, the NAD decrease was largely reduced by supplementation of NR (Figures 1A and 1B and S4A). Super-ovulated oocyte number was decreased in HFD mice compared with control mice (Figure 1C). Conversely, NR supplementation led to significantly more oocytes in HFD mice (Figure 1C) in comparison with HFD mice. Furthermore, more morphological defects as shown by fragments were observed in HFD oocytes compared with control oocytes, whereas such defects were attenuated due to supplementation of NR (Figure 1D and E). In addition, HFD mice gave birth to less offspring compared with controls. However, the subfertility of HFD mice were attenuated by administration of NR increased (Figure 1F). ROS content in MII oocytes was measured by using MitoSOX. The results showed that the ROS content was higher in HFD oocytes in comparison with controls, whereas NR supplementation significantly reduced ROS content in HFD oocytes (Figure 1G and H). MII oocytes