Sex modifies the consequences of extended fructose consumption on liver health, motor function, and physiological damage in rats

Abstract

Sex differences are evident in the presentation of metabolic symptoms. A shift of sex hormones that signal the onset of puberty combined with a poor diet consumed in adolescence is likely to have sex-specific, long-term impacts on adult physiology. Here, we expanded on existing literature to elucidate the sex-specific mechanisms driving physiological deficits following high fructose consumption. Male and female Wistar rats were fed a high-fructose (55%) diet beginning immediately postweaning for 10 wk. Female rats fed the high-fructose diet displayed elevated weight gain and extensive liver pathology consistent with markers of nonalcoholic fatty liver disease (NAFLD). Male rats fed the high-fructose diet exhibited increased circulating glucose along with moderate hepatic steatosis. Levels of cytokines and gene expression of inflammatory targets were not altered by fructose consumption in either sex. However, circulating levels of markers for liver health, including alanine transaminase and uric acid, and markers for epithelial cell death were altered by fructose consumption. From the alterations in these markers for liver health, along with elevated circulating triglycerides, it was evident that liver health had deteriorated significantly and that a number of factors were at play. Both adult fructose-fed male and female rats displayed motor deficits that correlated with aberrant structural changes at the neuromuscular junction; however, these deficits were exacerbated in males. These data indicate that consumption of a high-fructose diet beginning in adolescence leads to adult pathology that is modified by sex. Identification of these sex-specific changes has implications for treatment of clinical presentation of metabolic syndrome and related disorders.

Chronic high dietary sucrose induces sexually dimorphic metabolic adaptations in liver and adipose tissue

“…et al, 2015), yet worsened NAFLD severity in women (Ballestri et al, 2017). Indeed, our observation that the severity of sucrose-induced steatosis was greatest in female mice (Figure 2A and B) is in line with previous studies that report worsened steatosis in female rats following high fructose (Hyer et al, 2019), or high fat, high fructose diets (Chukijrungroat et al, 2017). Together with the observation that women increase de novo fatty acid synthesis in response to acute fructose ingestion whereas men do not (Low et al, 2018), our findings add physiologic insight as to why females develop more severe steatosis than males in response to high dietary sugar intake.…”

Sex Differences in Dietary Copper-Fructose Interaction-Induced Alterations of Gut Microbial Activity are Not Correlated to Hepatic Steatosis

“…In fact, the activities of liver enzymes involved in lipogenesis was affected not only by the type of carbohydrate, but also by the quantity (72). Lastly, differences in facilities, diet components and species as well as experimental durations may all contribute to discrepancy (25,73,74).…”

Macrophages in the pathophysiology of NAFLD: The role of sex differences

“…Indeed, Tran et al reported that the induction of very‐low‐density lipoproteins production and suppression of fatty acids oxidation after an oral load of fructose were less pronounced in pre‐menopausal women than in men 32 . Similarly, Hyer et al observed, in a murine model of fructose‐induced NAFLD, a more severe disease in males, further indicating a role of sex differences on carbohydrates liver metabolism in NAFLD 33 …”