Sex‐specific metabolic changes induced by high fructose corn syrup during adolescence: novel evidence from metabolomic and microbiome analyses in mice

Overconsumption of high fructose corn syrup (HFCS) in the form of an added sweetener in beverages has been strongly linked to the development of metabolic diseases, including obesity and non-alcoholic fatty liver diseases (NAFLD) (Pinnick & Hodson, 2019). Although high dietary sugar intake in general shows unfavourable metabolic outcomes, fructose in particular is gaining a worse reputation over time. Increasing evidence reveals that high fructose consumption contributes to increased body fat, dyslipidaemia, insulin resistance, increased oxidative stress and inflammation, all of which are key features of metabolic disorders (Pinnick & Hodson, 2019). More importantly, adolescents are prone to be affected by high fructose intake as they are in a vulnerable developmental window but also the major consumers of HFCS-added beverages (Pinnick & Hodson, 2019). In addition, changes in sex hormones with the onset of puberty may lead to sex-specific effects in the context of fructose overconsumption (Patton et al. 2006). Therefore, sex and age are the two key variables in fructose induced metabolic changes. However, few studies have focused on sex differences linked to high fructose intake in specific age groups, highlighting the need for future investigations to fill in the gaps. In a recent issue in The Journal of Physiology, Bhat et al. (2021) explored the effects of HFCS consumption in both male and female mice during adolescence (3–6 weeks old), and further examined if any of the outcomes persisted into adulthood (30 weeks old). At 3 weeks old, C57Bl/6J mice were fed with a standard chow diet supplemented with either water or 50% HFCS in water for 3 weeks. To examine the long-lasting effects, the mice were kept on a standard chow diet with water until 30 weeks old. Measurements from metabolic analyses, hepatic metabolomic profiling and gut microbiome analyses revealed that: (1) HFCS exposure during adolescence increased body weight, fat mass, glucose intolerance and hepatic fat in a sex-specific manner; (2) significant changes in hepatic metabolites and gut microbiome profiles were observed after 3 weeks of HFCS exposure, which differed with sex; (3) some of the changes lasted into adulthood long after HFCS exposure ceased. Sex differences in metabolic disorders are evident, especially in non-alcoholic fatty liver disease (NAFLD), given that oestrogen may have a protective effect against diet induced fatty liver (Patton et al. 2006). However, very few studies have focused on high fructose induced sex-specific changes in metabolic and liver health. Hyer et al. (2019) fed 3-week-old male and female rats with a high fructose diet (10% kcal fat; 55% kcal fructose) for 10 weeks and compared them with rats fed with standard chow diet. In agreement with Bhat et al. (2021), they found that females had greater increases in body weight and hepatic fat than males after high fructose exposure. In addition, Hyer et al. (2019) found that only female rats showed a significant increase in liver steatosis, ballooning and inflammation, indicating that females were more susceptible to fructose induced NAFLD. However, fructose fed females from both studies showed a better glucose homeostasis than males. Although, Bhat et al. (2021) did not show pathological liver changes, they conducted global metabolomic profiling in the liver to provide novel insights into sex-specific changes induced by fructose. One notable sex difference was found in bile acid profile changes, with females showing a significant decrease in bile acids while there were no changes in males. This may explain the higher fat mass in females as bile acids are key regulators in lipid metabolism (Bhat et al. 2021). Additionally, some dramatic changes in liver metabolites observed in females but not in males were linked to an increase in antioxidative defense, suggesting that female livers were more protected from oxidative stress after HFCS exposure. However, this cannot explain the higher liver damage found in females than in males. Also, the protective effect of oestrogen on female livers may be lost or masked during adolescence with high fructose intake. Fructose is known to impair liver health by altering the gut microbiota, although the underlying mechanisms are still not clear (Lambertz et al. 2017). Bhat et al. (2021) identified several sex-specific changes in the gut microbiome after HFCS exposure. In general, males showed more dramatic and persistent changes in the gut microbiome than females after 3 weeks of HFCS intake. Notably, most members in the bacteria family Ruminococcaceae were significantly reduced only in males, whereas only one member was reduced in females. Although a decrease in Ruminococcaceae in the gut microbiome was observed in patients with liver steatosis, it is still unclear how this links to lipid metabolic changes in the liver (Lambertz et al. 2017). Nevertheless, this study sheds light on sex differences in HFCS induced microbiome changes, highlighting an important role of the gut microbiome in sex-specific changes induced by fructose intake. Current evidence from human studies suggests that adolescents are highly vulnerable to the onset of NAFLD due to the decreases in adiponectin and insulin sensitivity, increases in sex hormones and changes in body fat distribution that occur during the normal course of puberty (Patton et al, 2006). The tendency to excessive fructose intake in adolescents further increases the risk of developing NAFLD and associated metabolic syndromes. In addition, the unfavourable metabolic changes developed in early life are likely to be carried into adulthood, as childhood obesity has a profound effect later in life (Patton et al. 2006). However, few studies have investigated age-specific and long-lasting effects of high fructose intake. To fill in this gap, Bhat et al. (2021) specifically focused on HFCS consumption in the adolescent age window and investigated whether any of the changes persisted into adulthood. Surprisingly, ∼75% of total metabolites measured in the liver were significantly altered by HFCS in both males and females, and 52 of them continued to be altered at 30 weeks age. Interestingly, at 30 weeks age, males fed with HFCS retained higher glucose intolerance, serum insulin and leptin compared to controls, despite their fat mass being restored to normal. In contrast, the fat mass in HFCS fed female mice remained high at 30 weeks of age, but their glucose tolerance remained normal and liver fat was restored to normal levels. As the authors suggest, the increased fat mass in females at 30 weeks age may be explained by the persistence of lower levels of bile acids. As most liver metabolites in males were maintained or restored to normal at 30 weeks of age, it is plausible that the persistent metabolic changes in males were caused by abnormalities in other tissues that suffered from long-lasting effects of HFCS exposure. Additional investigations of tissue-specific changes induced by HFCS would be helpful to elucidate the mechanisms behind these sex-specific long-lasting effects. As mentioned above, Bhat et al. (2021) demonstrated several long-lasting changes caused by short-term HFCS exposure during adolescence, which they considered alarming, but from another point of view, the data can also be interpreted more positively – many of the changes were restored to normal after removing HFCS from the diet, suggesting a positive preventitive/treatment effect of dietary changes simply by HFCS removal. Furthermore, the persistent changes revealed in this study provide potential targets for additional treatment or prevention strategies in addition to HFCS removal. For example, could HFCS removal combined with bile acid supplements restore the fat mass to normal levels in females at 30 weeks age? Exploring co-treatment strategies could be a promising approach for effective restoration of the long-lasting changes identified in this study. Identifying and understanding the sex- and age-specific metabolic changes caused by high fructose intake may provide distinct pathogenic mechanisms that can be used to develop new preventative and treatment strategies. By using high throughput omics approaches, Bhat et al. (2021) provided novel insights into the sex-specific metabolic changes and long-lasting effects of exposure to HFCS in adolescence that are highly relevant to the global trend of a high prevalence of obesity coupled with increased consumption of sweetened caloric beverages among teenagers (Patton et al. 2006). In addition, with increasing interest in precision medicine and personalized nutrition, specific changes identified in different age and sex groups will undoubtedly be valuable. Although the major experimental focus of this study was metabolomic and microbiome profiling, the lack of comprehensive pathological and physiological examinations (e.g. liver pathology, insulin resistance, etc.) made it difficult to assess the progression and severity of the liver conditions and metabolic impairment, and it also reduced its comparability to other studies with similar experimental settings. Overall, the novel insights provided by Bhat et al. (2021) provide a valuable basis for further exploration in both pre-clinical and clinical studies. It is possible that one day we will look back at use of refined sweeteners in the same way as we now look back at tobacco use. Maybe one day, feeding children above a certain level of refined sugars will be considered child abuse. However, it is only with a solid foundation of sufficient and powerful scientific evidence that these possibilities can be realised. Further investigations are urgently needed to reveal the sex and age differences in high fructose intake induced metabolic changes, as well as the mechanistic basis behind them. None declared. Sole author. C.W. holds a CBS International Graduate Research Assistantship and an International Doctoral Tuition Scholarship. None declared.

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