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The sperm quality in DIO male mice is linked to the NF-κB signaling and Ppp2ca expression in the hypothalamus

ABSTRACT: Emerging studies have reported a significant correlation between obesity and a decline in sperm quality among males, however, the underlying mechanism remains elusive. In this study, we observed that male mice with diet-induced obesity (DIO) exhibited functional alteration in the hypothalamic-pituitary-gonadal (HPG) axis, as evidenced by disruption of luteinizing hormone (LH) pulse release. This alteration was attributed to the activation of nuclear factor kappa B subunit (NF-κB) signaling in the hypothalamus, which subsequently led to a decline in sperm quality. The application of RNA-seq analysis in the hypothalamic arcuate nucleus (ARC) of DIO male mice has revealed a signaling network implicating protein phosphatase 2 catalytic subunit alpha (Ppp2ca), which is involved in the disruption of LH pulse secretion. Activation of NF-κB signaling increased expression, which decreased the Kiss1 expression through inhibition of Akt kinase (AKT) and cAMP responsive element binding protein 1 (CREB1) activities. Overexpression of the Ppp2ca gene in the hypothalamic ARC resulted in disrupted LH pulse secretion patterns and reduced sperm quality. Collectively, our findings provide novel insights into the molecular mechanisms underlying the decline in sperm quality observed in male DIO mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE284408 | GEO | 2025/03/05

REPOSITORIES: GEO

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Project description:Fertility critically depends on the gonadotropin-releasing hormone (GnRH) pulse generator, a neural construct comprised of hypothalamic neurons coexpressing kisspeptin, neurokoinin-B and dynorphin. Here, using mathematical modeling and in vivo optogenetics we reveal for the first time how this neural construct initiates and sustains the appropriate ultradian frequency essential for reproduction. Prompted by mathematical modeling, we show experimentally using female estrous mice that robust pulsatile release of luteinizing hormone, a proxy for GnRH, emerges abruptly as we increase the basal activity of the neuronal network using continuous low-frequency optogenetic stimulation. Further increase in basal activity markedly increases pulse frequency and eventually leads to pulse termination. Additional model predictions that pulsatile dynamics emerge from nonlinear positive and negative feedback interactions mediated through neurokinin-B and dynorphin signaling respectively are confirmed neuropharmacologically. Our results shed light on the long-elusive GnRH pulse generator offering new horizons for reproductive health and wellbeing.SIGNIFICANCE STATEMENT The gonadotropin-releasing hormone (GnRH) pulse generator controls the pulsatile secretion of the gonadotropic hormones LH and FSH and is critical for fertility. The hypothalamic arcuate kisspeptin neurons are thought to represent the GnRH pulse generator, since their oscillatory activity is coincident with LH pulses in the blood; a proxy for GnRH pulses. However, the mechanisms underlying GnRH pulse generation remain elusive. We developed a mathematical model of the kisspeptin neuronal network and confirmed its predictions experimentally, showing how LH secretion is frequency-modulated as we increase the basal activity of the arcuate kisspeptin neurons in vivo using continuous optogenetic stimulation. Our model provides a quantitative framework for understanding the reproductive neuroendocrine system and opens new horizons for fertility regulation Model is encoded by Johannes and submitted to BioModels by Ahmad Zyoud.

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The sperm quality in DIO male mice is linked to the NF-κB signaling and Ppp2ca expression in the hypothalamus

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