Abstract
BackgroundThe 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.MethodsAdult 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.ResultsThe 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.ConclusionsOur 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.
Highlights
The prevalence of obesity has steadily increased over the past three decades all over the world, and newly released data has showed that nearly one-third of the world’s population is obese or overweight [1]
Materials Primary and secondary antibodies applied in this study were introduced as follows: Silent information regulator related enzyme 1 (SIRT1), Forkhead box group O 3a (FOXO3a), Nuclear respiratory factor 1 (NRF-1), Mammalian target of rapamycin (mTOR), phospho-mTOR, phospho-p70S6 kinase α, NF-κB and p53 antibodies were obtained from Santa Cruz Biotechnology, USA; Silent information regulator related enzyme 6 (SIRT6) antibody was purchased from Abcam, UK; β-actin was obtained from Zhongshan Golden Bridge, Beijing, China; Secondary antibodies to mouse and rabbit IgG were purchased from Sigma, USA
All mice were alive at the end of 24-week treatment, and no superficial abnormalities or tumors were found in the abdomen and other parts of the body
Summary
The prevalence of obesity has steadily increased over the past three decades all over the world, and newly released data has showed that nearly one-third of the world’s population is obese or overweight [1]. Excess body fat ( abdominal obesity) is closely related to irregular menstrual cycles, reduced spontaneous conception and increased risk of miscarriage [4,5]. Our previous study demonstrated that obesity accelerated ovarian follicle development and follicle loss in female rats [10]. Childhood obesity has a negative effect on reproduction, which may lead to early onset of puberty, menstrual irregularities during adolescence and polycystic ovary syndrome [14]. These studies shed light on the negative effects of obesity on the reproductive functions in females. 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
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