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

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.

mTORC1/2 Inhibition Preserves Ovarian Function and Fertility During Genotoxic Chemotherapy

“…Data implicate mTOR up-regulation in the poor reproductive outcomes of overweight and obese patients, who are more likely to be infertile, have higher miscarriage rates, and poorer obstetric outcomes compared with normal-weight peers (32)(33)(34). Obese rats demonstrate accelerated ovarian follicle development and follicle loss and activation of the mTOR pathway (35), whereas SIRT1 activators, which suppress mTOR, improve the ovarian reserve (36). Caloric restriction in rats also down-regulates mTOR activity and preserves the ovarian reserve (37).…”

Resveratrol Protects Against Pulmonary Arterial Hypertension in Rats via Activation of Silent Information Regulator 1

“…The dosage of SRT1720 (25 mg/kg/day) was chosen according to several research studies. Zhou et al suggested that a high dose of SRT1720 (50 mg/kg) could improve obesity induced by a high-fat diet in mice [47]. Minor et al indicated that either a high dose of SRT1720 (100 mg/kg) or a low dose of SRT1720 (30 mg/kg) could improve survival and longevity in obese mice [48].…”

The Role and Application of Sirtuins and mTOR Signaling in the Control of Ovarian Functions

“…The pharmacological activation of SIRT1 and SIRT6 prevented the age-dependent exhaustion of rat [11] and mice [12] follicle reserve.…”

“…The mTOR blockers resveratrol and rapamycin can promote the accumulation of both SIRT1 and SIRT6 in ovarian cells [10,11]. On the other hand, SIRT1 can suppress mTOR activity within non-ovarian [8] and ovarian [12] cells. The data concerning interrelationships between mTOR and other SIRTs within the ovary have not yet been reported.…”

“…SIRTs affect these processes via the down-regulation of a serine/threonine kinase called mammalian target of rapamycin (mTOR) [8,9] and other intracellular signaling pathways [5], although mTOR can in turn up-regulate SIRTs production [9,10,11,12]. Recently, SIRTs and their regulators have been intensively studied to examine the potential of SIRTs to be diagnostic and predictive indexes for some disorders, and to be useful for the treatment of malignant and metabolic disorders.…”