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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.

Zhou XL, Xu JJ, Ni YH, Chen XC, Zhang HX, Zhang XM, Liu WJ, Luo LL, Fu YC - J Ovarian Res (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

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Related in: MedlinePlus

Comparison of ovarian follicles at each stage among groups. (A) The mean number of ovarian follicles at each stage among groups. (B) Percentage of ovarian follicles at each stage among groups. Data were presented as mean ± S.E.M. *P < 0.05, **P < 0.01, ***P < 0.001 vs. the NC group.
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Fig5: Comparison of ovarian follicles at each stage among groups. (A) The mean number of ovarian follicles at each stage among groups. (B) Percentage of ovarian follicles at each stage among groups. Data were presented as mean ± S.E.M. *P < 0.05, **P < 0.01, ***P < 0.001 vs. the NC group.

Mentions: The mean number and percentage of primordial follicles in the SRT1720 group were more than those of the NC group (21.5 ± 1.1 vs. 13.1 ± 1.1; 11.4% ±0.7% vs. 7.7% ±0.6%, P < 0.001, respectively), while those of the CHF group and the NAM group were less than those of the NC group (6.8 ± 0.3, 9.5 ± 1.1 vs. 13.1 ± 1.1, P < 0.001, P < 0.05, respectively; 2.7% ±0.1%, 4.5% ± 0.6% vs. 7.7% ± 0.6%, P < 0.001, P < 0.01, respectively). Although the SRT1720 group had a similar mean number of primordial follicles to the CR group (21.5 ± 1.1 vs. 25.6 ± 1.0, P > 0.05), it had less percentage of primordial follicles than the CR group (11.4% ±0.7% vs. 16.2% ±0.6%, P < 0.001). The mean number and percentage of developing follicles (including primary, secondary and antral follicles) were comparable among groups (P > 0.05). The number and percentage of corpora lutea in the SRT1720 group were similar to those of the NC group (46.2 ± 4.3 vs. 40.5 ± 3.4; 24.6% ±2.8% vs. 24.1% ±2.1%, P > 0.05, respectively), but less than those of the CHF and NAM group (46.2 ± 4.3 vs. 92.1 ± 4.9, 72.3 ± 5.0, P < 0.001, respectively; 24.6% ±2.8% vs. 37.0% ±1.8%, 34.6% ±4.4%; P < 0.01, respectively). The CR group had less corpora lutea than the NC group (17.9 ± 4.7 vs. 40.5 ± 3.4; 11.6% ±1.5% vs. 24.6% ±2.8%, P < 0.01, respectively) (Figure 5).Figure 5


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.

Zhou XL, Xu JJ, Ni YH, Chen XC, Zhang HX, Zhang XM, Liu WJ, Luo LL, Fu YC - J Ovarian Res (2014)

Comparison of ovarian follicles at each stage among groups. (A) The mean number of ovarian follicles at each stage among groups. (B) Percentage of ovarian follicles at each stage among groups. Data were presented as mean ± S.E.M. *P < 0.05, **P < 0.01, ***P < 0.001 vs. the NC group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4232623&req=5

Fig5: Comparison of ovarian follicles at each stage among groups. (A) The mean number of ovarian follicles at each stage among groups. (B) Percentage of ovarian follicles at each stage among groups. Data were presented as mean ± S.E.M. *P < 0.05, **P < 0.01, ***P < 0.001 vs. the NC group.
Mentions: The mean number and percentage of primordial follicles in the SRT1720 group were more than those of the NC group (21.5 ± 1.1 vs. 13.1 ± 1.1; 11.4% ±0.7% vs. 7.7% ±0.6%, P < 0.001, respectively), while those of the CHF group and the NAM group were less than those of the NC group (6.8 ± 0.3, 9.5 ± 1.1 vs. 13.1 ± 1.1, P < 0.001, P < 0.05, respectively; 2.7% ±0.1%, 4.5% ± 0.6% vs. 7.7% ± 0.6%, P < 0.001, P < 0.01, respectively). Although the SRT1720 group had a similar mean number of primordial follicles to the CR group (21.5 ± 1.1 vs. 25.6 ± 1.0, P > 0.05), it had less percentage of primordial follicles than the CR group (11.4% ±0.7% vs. 16.2% ±0.6%, P < 0.001). The mean number and percentage of developing follicles (including primary, secondary and antral follicles) were comparable among groups (P > 0.05). The number and percentage of corpora lutea in the SRT1720 group were similar to those of the NC group (46.2 ± 4.3 vs. 40.5 ± 3.4; 24.6% ±2.8% vs. 24.1% ±2.1%, P > 0.05, respectively), but less than those of the CHF and NAM group (46.2 ± 4.3 vs. 92.1 ± 4.9, 72.3 ± 5.0, P < 0.001, respectively; 24.6% ±2.8% vs. 37.0% ±1.8%, 34.6% ±4.4%; P < 0.01, respectively). The CR group had less corpora lutea than the NC group (17.9 ± 4.7 vs. 40.5 ± 3.4; 11.6% ±1.5% vs. 24.6% ±2.8%, P < 0.01, respectively) (Figure 5).Figure 5

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus