title: SIRT1 activator (SRT1720) improves the follicle reserve and prolongs the ovarian lifespan of diet-induced obesity in female mice via activating SIRT1 and suppressing mTOR signaling.
abstract: BACKGROUND
  The prevalence of obesity is increasing worldwide and significantly affects fertility and reproduction in both men and women. Our recent study has shown that excess body fat accelerates ovarian follicle development and follicle loss in rats. The aim of the present study is to explore the effect of SIRT1 activator SRT1720 on the reserve of ovarian follicle pool and ovarian lifespan of obese mice and the underlying mechanism associated with SIRT1 and mTOR signaling.
  
  
  METHODS
  Adult female Kunming mice (n = 36) were randomly divided into three groups: the normal control (NC) group (n = 8), the caloric restriction (CR) group (fed 70% food of the NC group, n = 8) and the high-fat diet (HF) group (fed a rodent chow containing 20% fat, n = 20). After 4 months, the HF mice were further randomly divided into three groups: the control high-fat diet (CHF, n = 8) group (treated every day with an intraperitoneal injection of vehicle), the SRT1720 (SRT, n = 6) group (treated every other day with an intraperitoneal injection of SRT1720 (50 mg/kg)), the SRT1720 and nicotinamide (NAM, n = 6) group (treated every other day with an intraperitoneal injection of SRT1720 (50 mg/kg) and every day with an intraperitoneal injection of nicotinamide (100 mg/kg)). After 6 weeks of treatment, ovaries were harvested for histological and Western blotting analyses.
  
  
  RESULTS
  The body weight, ovary weight and visceral fat in the SRT group were significantly lower than those in the CHF group at the end of treatment. Histological analysis showed that the SRT mice had significantly greater number and percentage of primordial follicles, but lower number and percentage of corpora lutea and atretic follicles than the CHF mice and NAM mice. Western blot analysis demonstrated that the levels of SIRT1, SIRT6, FOXO3a and NRF-1 protein expression significantly increased in the ovaries of SRT mice, whereas those of mTORC1, p-mTOR, p-p70S6K, NFκB and p53 decreased compared to the CHF and NAM mice.
  
  
  CONCLUSIONS
  Our study suggests that SRT1720 may improve the follicle pool reserve in HF diet-induced obese female mice via activating SIRT1 signaling and suppressing mTOR signaling, thus extending the ovarian lifespan.
authors.affiliation: Department of Gynaecology and Obstetrics of the First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong Province, 515041, People's Republic of China. xlzhou1314@163.com.
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Zhou
authors.affiliation: Laboratory of Cell Senescence, Shantou University Medical College, 22 Xin Ling Rd, Jinping District, Shantou, Guangdong Province, 515041, People's Republic of China. jjxu1988@163.com.
authors.forename: Jin-Jie
authors.initials: JJ
authors.lastname: Xu
authors.affiliation: Department of Gynaecology and Obstetrics of the First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong Province, 515041, People's Republic of China. 13yhni@stu.edu.cn.
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Ni
authors.affiliation: Department of Gynaecology and Obstetrics of the First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong Province, 515041, People's Republic of China. victoria52020@163.com.
authors.forename: Xiao-Chun
authors.initials: XC
authors.lastname: Chen
authors.affiliation: Department of Gynaecology and Obstetrics of the First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong Province, 515041, People's Republic of China. 08hxzhang@stu.edu.cn.
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Zhang
authors.affiliation: Department of Gynaecology and Obstetrics of Huizhou Municipal Central Hospital, Huizhou, Guangdong Province, 516001, People's Republic of China. xmzhang057@163.com.
authors.forename: Xing-Mei
authors.initials: XM
authors.lastname: Zhang
authors.affiliation: Department of Gynaecology and Obstetrics of the First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong Province, 515041, People's Republic of China. hyklwj@163.com.
authors.forename: Wei-Juan
authors.initials: WJ
authors.lastname: Liu
authors.affiliation: Department of Gynaecology and Obstetrics of the First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong Province, 515041, People's Republic of China. luolili6606@163.com.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Luo
authors.affiliation: Laboratory of Cell Senescence, Shantou University Medical College, 22 Xin Ling Rd, Jinping District, Shantou, Guangdong Province, 515041, People's Republic of China. ycfu@stu.edu.cn.
authors.forename: Yu-Cai
authors.initials: YC
authors.lastname: Fu
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D020536:Enzyme Activators / Q000494:pharmacology; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D005300:Fertility Agents, Female / Q000494:pharmacology*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D007247:Infertility, Female / Q000188:drug therapy* / Q000209:etiology; D050152:Intra-Abdominal Fat / Q000473:pathology; D051379:Mice; D009765:Obesity / Q000150:complications*; D009929:Organ Size; D065851:Ovarian Reserve / Q000187:drug effects; D010053:Ovary / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D020536:Enzyme Activators; D005300:Fertility Agents, Female; D006576:Heterocyclic Compounds, 4 or More Rings; C525422:SRT1720; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1