Wang Shuo, Zhang Xinhui, Zhang Lingling, Zhuo Shixuan, Chen Yan
Shanghai Institute of Nutrition and HealthUniversity of Chinese Academy of SciencesShanghaiPeople's Republic of China.
Am J Physiol Endocrinol Metab. 2025 Sep 1;329(3):E393-E404. doi: 10.1152/ajpendo.00096.2025. Epub 2025 Jul 25.
Sexual dimorphism in glucose metabolism is increasingly recognized as a critical factor in metabolic homeostasis. Our prior study has highlighted the role of intestinal monocarboxylate transporter 1 (MCT1) in mediating lactate transport and its sex-specific effect on glucose metabolism in mice. Here, we investigated the sex-specific metabolic flux in the intestine and its impact on postprandial lactate shuttle and glucose homeostasis. Using a combination of isotopic tracing techniques and in vivo experiments, we discovered that intestinal epithelium exhibits sex-specific metabolic profiles, leading to differential glucose metabolism. Female mice displayed higher oxidative phosphorylation activity and greater utilization of lactate/pyruvate in the tricarboxylic acid (TCA) cycle than male mice, resulting in improved glucose tolerance. In contrast, male mice exhibited higher glycolytic activity with an increased postprandial lactate level, correlating with poorer glucose tolerance than female mice. Estrogen treatment in male mice reduced intestinal interstitial lactate level and improved glucose tolerance. Castration of male mice also improved glucose tolerance, whereas androgen replacement reversed this effect. Conversely, ovariectomy in female mice impaired glucose tolerance, which was restored by estrogen replacement. Our findings thus underscore the importance of sex-specific glucose metabolism in the intestine and its implications for metabolic health, laying a foundation for developing sex-specific therapeutic strategies for metabolic disorders. Sex dimorphic difference in glucose homeostasis has been well recognized; however, how glucose metabolism in the intestine contributes to this phenomenon is poorly known. We discovered that the male mice have an elevated rate of glycolysis in the intestine, whereas the female mice have an increased rate of oxidative phosphorylation, contributing to the sex difference in glucose tolerance. In addition, sex hormones are crucial in mediating such a difference between the two sexes.
葡萄糖代谢中的性别二态性日益被认为是代谢稳态的关键因素。我们之前的研究强调了肠道单羧酸转运体1（MCT1）在介导乳酸转运中的作用及其对小鼠葡萄糖代谢的性别特异性影响。在此，我们研究了肠道中性别特异性的代谢通量及其对餐后乳酸穿梭和葡萄糖稳态的影响。通过结合同位素示踪技术和体内实验，我们发现肠道上皮表现出性别特异性的代谢特征，导致葡萄糖代谢存在差异。雌性小鼠在三羧酸（TCA）循环中显示出比雄性小鼠更高的氧化磷酸化活性和对乳酸/丙酮酸的更大利用，从而导致葡萄糖耐量提高。相比之下，雄性小鼠表现出更高的糖酵解活性，餐后乳酸水平升高，这与比雌性小鼠更差的葡萄糖耐量相关。对雄性小鼠进行雌激素治疗可降低肠道间质乳酸水平并改善葡萄糖耐量。对雄性小鼠进行去势也可改善葡萄糖耐量，而雄激素替代则逆转了这种作用。相反，对雌性小鼠进行卵巢切除会损害葡萄糖耐量，而雌激素替代可恢复这种耐量。因此，我们的研究结果强调了肠道中性别特异性葡萄糖代谢的重要性及其对代谢健康的影响，为开发针对代谢紊乱的性别特异性治疗策略奠定了基础。葡萄糖稳态中的性别二态性差异已得到充分认识；然而，肠道中的葡萄糖代谢如何导致这一现象却鲜为人知。我们发现雄性小鼠肠道中的糖酵解速率升高，而雌性小鼠的氧化磷酸化速率增加，这导致了葡萄糖耐量的性别差异。此外，性激素在介导两性之间的这种差异方面至关重要。
