Sustained High Protein-Tyrosine Phosphatase 1B Activity in the Sperm of Obese Male Impairs the Sperm Acrosome Reaction [Molecular Bases of Disease]

February 11th, 2014 by Shi, L., Zhang, Q., Xu, B., Jiang, X., Dai, Y., Zhang, C.-Y., Zen, K.

Evidence of a causal link between male obesity and sub-fertility or infertility has been previously demonstrated. However, the mechanism underlying this link is incompletely understood. Here, we report that sustained high protein-tyrosine phosphatase 1B (PTP1B) activity in sperm of obese donors plays an essential role in coupling male obesity and sub-fertility or infertility. First, PTP1B level and activity were significantly higher in sperm from ob/ob mice than wild-type littermates. High PTP1B level and activity in sperm was also observed in obese patients compared to non-obese donors. The enhanced sperm PTP1B level and activity in ob/ob mice and obese patients correlated with a defect of the sperm acrosome reaction (AR). Second, treating sperm from male ob/ob mice or obese men with a specific PTP1B inhibitor largely restored the sperm AR. Finally, blockade of sperm AR by enhanced PTP1B activity in male ob/ob mice or obese men was due to prolonged de-phosphorylation of N-ethylmaleimide- sensitive factor (NSF) by PTP1B, leading to the inability to reassemble the trans-SNARE complexes, which is a critical step in sperm acrosomal exocytosis. In summary, our study demonstrates for the first time that a sustained high PTP1B level or activity in the sperm of obese donors causes a defect of sperm AR and that PTP1B is a novel potential therapeutic target for male infertility treatment.
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