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Dapagliflozin Ameliorates Ovulation Disorders via Attenuating Activated Microglia-Mediated Hypothalamic Inflammation
Xiaolin Chen1, Zhuoni Xiao2, Qing Liu2
1Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, China.
Introduction:
Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have shown neuroprotective effects in obese mice. However, whether SGLT2i can ameliorate high-fat diet (HFD)-related ovulation disorders remains unknown. The aim of this research was to investigate whether dapagliflozin improves HFD-induced ovulatory dysfunction by attenuating microglia-mediated hypothalamic inflammation.
Methods:
C57BL/6J female mice fed HFD were treated with dapagliflozin (1 mg/kg) for 22 weeks. Plasma insulin, leptin, luteinizing hormone (LH), estradiol (E2), and IL-1β levels were also tested. Microglial morphology, cell numbers, and SGLT2 expression were evaluated using immunofluorescence. The expression of IL-1β, NLRP3, kisspeptin, gonadotropin-releasing hormone (GnRH), SGLT2, insulin, and leptin receptors in the hypothalamus was determined using immunohistochemical staining. We also examined the effects of dapagliflozin on glucose metabolism and the release of inflammatory factor in palmitic acid (PA)-treated HMC3 cells.
Results:
As expected, dapagliflozin improved HFD-induced metabolic disturbances, peripheral versus central insulin and leptin resistance and also restored the regular estrous cycle. Furthermore, dapagliflozin blunted microglia activation, NLRP3 inflammasome priming, hypothalamic inflammation, and increased the expression of GnRH and kisspeptin at proestrus in the hypothalamus. Additionally, dapagliflozin markedly reduced IL-6 and NO release and fat accumulation, decreased lactic acid production and glucose consumption, and inhibited mammalian target of rapamycin (mTOR) and hexokinase 2 (HK2) expression in PA-treated HMC3 cells. These effects suggest that dapagliflozin reduced the mTOR/HK2-mediated aerobic glycolysis.
Conclusions:
Dapagliflozin improved HFD-related ovulation disorders by regulating glucose metabolism through mTOR/HK2 signaling and attenuating microglia-mediated hypothalamic inflammation. These results validate the novel role for the neuroprotection of SGLT2i in HFD-induced obesity and ovulation disorders.
Insights
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) like dapagliflozin can improve ovulation disorders caused by high-fat diets. This is achieved by regulating glucose metabolism and reducing brain inflammation, offering neuroprotection in obesity.
Area of Science:
- Neuroendocrinology
- Metabolic disorders
- Pharmacology
Background:
- High-fat diets (HFD) induce obesity and can lead to ovulation disorders.
- Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated neuroprotective effects.
- The impact of SGLT2i on HFD-related ovulation dysfunction is not well understood.
Purpose of the Study:
- To investigate if dapagliflozin can improve HFD-induced ovulatory dysfunction.
- To determine if dapagliflozin attenuates microglia-mediated hypothalamic inflammation.
- To explore the underlying mechanisms involving glucose metabolism and inflammation.
Main Methods:
- Female C57BL/6J mice were fed HFD and treated with dapagliflozin for 22 weeks.
- Evaluated metabolic parameters, hormonal levels, and estrous cycle regularity.
- Assessed hypothalamic microglia activation, inflammation markers, and neurotransmitter expression via immunofluorescence and immunohistochemistry.
- Examined dapagliflozin's effects on glucose metabolism and inflammatory factors in palmitic acid-treated HMC3 cells.
Main Results:
- Dapagliflozin improved HFD-induced metabolic disturbances, insulin/leptin resistance, and restored estrous cycles.
- Dapagliflozin reduced microglia activation, NLRP3 inflammasome priming, and hypothalamic inflammation.
- Increased hypothalamic expression of GnRH and kisspeptin was observed.
- In vitro, dapagliflozin reduced inflammatory factors and inhibited mTOR/HK2-mediated aerobic glycolysis.
Conclusions:
- Dapagliflozin ameliorates HFD-related ovulation disorders by regulating glucose metabolism via mTOR/HK2 signaling.
- Dapagliflozin attenuates microglia-mediated hypothalamic inflammation, demonstrating neuroprotective effects.
- These findings highlight a novel role for SGLT2 inhibitors in managing obesity-associated reproductive dysfunction.
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