Department of Pediatrics, Christiana Care Health System, Newark, DE, USA.
Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
J Physiol. 2021 Mar;599(5):1487-1511. doi: 10.1113/JP280034. Epub 2021 Feb 4.
The prevalence of obesity and non-alcoholic fatty liver disease in children is dramatically increasing at the same time as consumption of foods with a high sugar content. Intake of high fructose corn syrup (HFCS) is a possible aetiology as it is thought to be more lipogenic than glucose. In a mouse model, HFCS intake during adolescence increased fat mass and hepatic lipid levels in male and female mice. However, only males showed impaired glucose tolerance. Multiple metabolites including lipids, bile acids, carbohydrates and amino acids were altered in liver in a sex-specific manner at 6 weeks of age. Some of these changes were also present in adulthood even though HFCS exposure ended at 6 weeks. HFCS significantly altered the gut microbiome, which was associated with changes in key microbial metabolites. These results suggest that HFCS intake during adolescence has profound metabolic changes that are linked to changes in the microbiome and these changes are sex-specific.
The rapid increase in obesity, diabetes and fatty liver disease in children over the past 20 years has been linked to increased consumption of high fructose corn syrup (HFCS), making it essential to determine the short- and long-term effects of HFCS during this vulnerable developmental window. We hypothesized that HFCS exposure during adolescence significantly impairs hepatic metabolic signalling pathways and alters gut microbial composition, contributing to changes in energy metabolism with sex-specific effects. C57bl/6J mice with free access to HFCS during adolescence (3-6 weeks of age) underwent glucose tolerance and body composition testing and hepatic metabolomics, gene expression and triglyceride content analysis at 6 and 30 weeks of age (n = 6-8 per sex). At 6 weeks HFCS-exposed mice had significant increases in fat mass, glucose intolerance, hepatic triglycerides (females) and de novo lipogenesis gene expression (ACC, DGAT, FAS, ChREBP, SCD, SREBP, CPT and PPARα) with sex-specific effects. At 30 weeks, HFCS-exposed mice also had abnormalities in glucose tolerance (males) and fat mass (females). HFCS exposure enriched carbohydrate, amino acid, long chain fatty acid and secondary bile acid metabolism at 6 weeks with changes in secondary bile metabolism at 6 and 30 weeks. Microbiome studies performed immediately before and after HFCS exposure identified profound shifts of microbial species in male mice only. In summary, short-term HFCS exposure during adolescence induces fatty liver, alters important metabolic pathways, some of which continue to be altered in adulthood, and changes the microbiome in a sex-specific manner.
肥胖和非酒精性脂肪性肝病在儿童中的流行率与高糖含量食物的消费同时急剧增加。摄入高果糖玉米糖浆（HFCS）可能是一种病因，因为它比葡萄糖更具脂肪生成性。在青春期摄入 HFCS 会增加雄性和雌性小鼠的脂肪量和肝内脂质水平。然而，只有雄性表现出葡萄糖耐量受损。在 6 周龄时，肝脏中的多种代谢物（包括脂质、胆汁酸、碳水化合物和氨基酸）以性别特异性方式发生改变。其中一些变化在成年期也存在，尽管 HFCS 暴露在 6 周时结束。HFCS 显著改变了肠道微生物组，这与关键微生物代谢物的变化有关。这些结果表明，青春期摄入 HFCS 会导致深刻的代谢变化，这些变化与微生物组的变化有关，而且这些变化具有性别特异性。
在过去的 20 年中，儿童肥胖、糖尿病和脂肪肝的迅速增加与高果糖玉米糖浆（HFCS）的消费增加有关，因此必须确定 HFCS 在这一脆弱的发育期的短期和长期影响。我们假设青春期暴露于 HFCS 会显著损害肝脏代谢信号通路并改变肠道微生物组成，从而导致能量代谢的变化，具有性别特异性影响。自由摄入 HFCS 的 C57bl/6J 小鼠在青春期（3-6 周龄）进行葡萄糖耐量和身体成分测试，并在 6 和 30 周龄（n=6-8 只/性别）时进行肝脏代谢组学、基因表达和甘油三酯含量分析。在 6 周龄时，HFCS 暴露的小鼠体脂增加、葡萄糖耐量降低、肝内甘油三酯增加（雌性）和从头脂肪生成基因表达增加（ACC、DGAT、FAS、ChREBP、SCD、SREBP、CPT 和 PPARα），具有性别特异性影响。在 30 周龄时，HFCS 暴露的小鼠也表现出葡萄糖耐量异常（雄性）和体脂增加（雌性）。HFCS 暴露在 6 周时富集碳水化合物、氨基酸、长链脂肪酸和次级胆汁酸代谢，在 6 和 30 周时次级胆汁代谢发生变化。HFCS 暴露前和暴露后的微生物组研究仅在雄性小鼠中鉴定出微生物物种的深刻变化。总之，青春期短期 HFCS 暴露会导致脂肪肝，改变重要的代谢途径，其中一些在成年期仍继续改变，并以性别特异性的方式改变微生物组。
