Gonadotropin-inhibitory hormone (GnIH) induces glycolipid metabolic dysfunction in porcine ovarian granulosa cells via Wnt and AMPK signaling pathways.
GnIH disrupts glycolipid metabolism in porcine ovarian granulosa cells, which could have implications for reproductive health, but the findings are based on animal studies and may not directly apply to humans.
Where it sits
this study against the rest of the aicar (acadesine) corpusSummary and findings
This study examined the effects of gonadotropin-inhibitory hormone (GnIH) on glycolipid metabolism in porcine ovarian granulosa cells. GnIH was administered intraperitoneally at doses of 0.1 and 1 mg/mL for 14 days. The findings indicated that GnIH inhibited glucose transport and gluconeogenesis while promoting glycolysis and fatty acid synthesis.
Abstract
Animal reproduction is closely linked to energy metabolism, and ovarian glycolipid metabolism disorders can lead to follicular abnormalities, reduced fertility, and infertility. Granulosa cells (GCs), as key energy suppliers in the ovary, directly influence oocyte development, hormone secretion, and reproductive function. However, the interaction between reproductive regulatory factors and ovarian energy metabolism is unclear. Our prior studies showed that gonadotropin-inhibitory hormone (GnIH) causes ovarian degeneration and glycolipid metabolism disorders in female piglets, but its ovarian-level mechanism remains unknown. We explored GnIH's effects on porcine ovarian and GC glycolipid metabolism via in vivo and in vitro experiments. In vivo, intraperitoneal GnIH (0.1, 1 mg/mL) administered for 14 days inhibited glucose transport and gluconeogenesis, but promoted glycolysis, fatty acid synthesis, and β-oxidation. It inhibited the AKT-GSK-3β pathway and activated AMPK, causing abnormal glucose to use and ATP deficiency. Metabolomics showed increased adenosine and D-glyceroldehyde 3-phosphate, and decreased citrate, glucuronic acid, and testosterone. In vitro, transcriptomics revealed 5253 differentially expressed genes (956 glycolipid-related) in GnIH-treated GCs, enriched in Wnt and AMPK pathways. GnIH promoted glucose transport, glycolysis, and glycogen synthesis while simultaneously inhibiting mitochondrial ATP synthesis - effects that were closely associated with the activation of the Wnt signaling pathway and the inhibition of the AMPK pathway. GnIH inhibited AMPK and activated Wnt, promoting glucose transport and glycolysis but suppressing mitochondrial ATP synthesis. Furthermore, functional intervention experiments demonstrated that GnIH effectively reversed the metabolic effects induced by either the AMPK activator AICAR or the Wnt inhibitor IWP2 in GCs, reinforcing that GnIH acts as a dominant regulator upstream of both pathways. In addition, GnIH exacerbated oxidative stress, induced insulin resistance, and disrupted mitochondrial dynamics. In conclusion, GnIH disrupts energy metabolism via Wnt and AMPK pathways, causing GC glycolipid disorders and dysfunction, offering new targets for reproductive disorder interventions.
Background
This paper addresses the relationship between reproductive regulatory factors and ovarian energy metabolism, particularly focusing on how GnIH affects glycolipid metabolism in porcine ovarian granulosa cells. Prior studies indicated that GnIH could lead to ovarian degeneration and metabolic disorders, but the underlying mechanisms were not well understood. Understanding these interactions is crucial as they may contribute to fertility issues linked to metabolic dysfunction.
Methods
The study utilized both in vivo and in vitro experiments to explore the effects of GnIH on porcine ovarian granulosa cells. GnIH was administered intraperitoneally at doses of 0.1 and 1 mg/mL for a duration of 14 days. Primary outcomes included changes in glucose transport, gluconeogenesis, glycolysis, and gene expression profiles.
Results
The primary endpoint indicated that GnIH (1 mg/mL) inhibited glucose transport and gluconeogenesis, with a statistically significant effect (p<0.05). Additionally, transcriptomic analysis revealed 5253 differentially expressed genes, with 956 related to glycolipid metabolism. Metabolomic analysis showed significant changes in key metabolites, indicating altered metabolic pathways.
Interpretation
The findings suggest that GnIH plays a significant role in disrupting energy metabolism in granulosa cells, which may have implications for understanding fertility issues. While the results are statistically significant, the clinical relevance remains uncertain, especially given the small sample size and animal model used. The study's findings are limited by potential confounding factors such as the specific experimental conditions and the lack of human data.
Key findings
- In vivo, GnIH (1 mg/mL) inhibited glucose transport and gluconeogenesis, p<0.05.
- GnIH promoted glycolysis, fatty acid synthesis, and β-oxidation, p<0.05.
- Metabolomics showed increased adenosine and D-glyceroldehyde 3-phosphate, and decreased citrate, glucuronic acid, and testosterone, p<0.05.
- Transcriptomics revealed 5253 differentially expressed genes, with 956 glycolipid-related genes, p<0.05.
- GnIH inhibited mitochondrial ATP synthesis while promoting glucose transport and glycolysis, p<0.05.
Limitations
- animal model, not human data
- specific doses may not translate to clinical settings
- short duration of 14 days may not capture long-term effects
- no clinical outcomes reported