According to the WHO claims, the prevalence of overweight and obesity has become a worldwide public health issue [1]. Epidemiological studies reveal that alterations in the composition and availability of food are the prominent driving force [2]. Since the 1970s, both sugar and high-fat diets have been viewed as the important drivers of excess energy intake which usually leads to obesity and its associated hepatic steatosis and insulin resistance [3,4]. Both energy balance and carbohydrate-insulin models regarding obesity pathogenesis target processed carbohydrates as major drivers of obesity [5,6]. Sugar-sweetened beverages are a priority concern given their relationship with obesity [7]. Nowadays, the added-sugar is usually in the form of sucrose or high-fructose corn syrup (HFCS), both of which are composed of nearly equal amounts of glucose and fructose, but HFCS seems to own a more complicated metabolic fate. Despite both of them are six-carbon sugars, glucose and fructose are metabolized via divergent pathways with distinct metabolic consequences [8,9]. Unlike glucose, fructose is not an insulin secretagogue and its metabolism is largely independent of insulin regulation [10]. Most of the dietary fructose is cleared by the small intestine and liver, where it can bypass glycolysis - a rate-limiting step in acetyl-CoA production [11]. Therefore, fructose metabolism leads to rapid generation of high levels of acetyl-CoA, some of which can be directed towards de novo lipogenesis (DNL), and increased DNL may contribute to the development of steatosis [12]. In addition, malonyl-CoA, an intermediate metabolite of DNL, plays a pivotal role as a signaling molecule via effectively inhibiting carnitine palmitoyltransferase 1A (Cpt1a), an essential enzyme for transporting fatty acids into the mitochondria. Consequently, fructose-derived signals can feedback inhibition fatty acid β-oxidation, which also contributes to the onset of steatosis [13]. Consumption of fructose-sweetened beverages has been found to be closely associated with non-alcoholic fatty liver disease (NAFLD). Individuals consuming sugar-sweetened beverages at least once a week experience a 77% higher likelihood of developing NAFLD compared to those who do not drink such beverages [14]. In contrast, a nine-day restriction of fructose in children with a high baseline fructose consumption resulted in reduced liver fat and decreased de novo lipogenesis compared to controls fed an isocaloric diet [15]. Therefore, fructose should be a major mediator of NAFLD.

Mountains of evidence suggest that excess fat and sugar promote calorie intake and body weight gain, high-fat high-sugar diet may be far more its apparent harmlessness and requires more attention. Similarly, the rising incidence rates of obesity and associated complications suggest that its pathogenesis is a multifaceted and intricate process, and underscore a deep understanding of the risks behind the high-calorie diet metabolic adaptation. As for pathogenesis research, a high-fat diet or a high-fat high-sugar diet is usually used for inducing an experimental animal model of obesity, whereas a high-fat diet coupled with a HFCS-sweetened drink is most popular which mirrors one normal dietary habit of modern individuals [16]. Dietary fat is considered a crucial factor in the pathogenesis of obesity, which provides an abundance of free fatty acids (FFAs) and directly promotes liver triglycerides accumulation, and studies also suggest that HFCS intake increases de novo lipogenesis and insulin resistance [17,18]. However, the synergistic effects of dietary fat and HFCS in promoting the development of obesity, dyslipidemia, and insulin resistance have not been fully elucidated. Likewise, for the mechanistic understanding of obesity, diet-induced obesity (DIO) models are most frequently used, thus multifarious recipes varied in the source and proportion of fat and sugars have emerged [19]. As for the experimental species, considering its physiology is closer to human being, DIO mice and rats are the most popular under various conditions [20]. Furthermore, if similar results are observed in both species, it will provide a more compelling rationale for translating the results.

In our earlier investigations, we have revealed that the HFF diet dysregulates the homeostatic crosstalk between gut microbiome, metabolome and immunity in an experimental rat model of obesity, as well as some potential small molecular messengers in the liver-gut axis [18]. However, the underlying mechanisms and risks behind the adaptation to HFF, for example, the derived lipotoxicity, remain inadequately characterized. Herein, in the present study, a comparative transcriptomic analysis was carried out, including the HFF diet challenged rats and mice against the normal chow fed animals. In addition, some other public transcriptional profiles challenged by different experimental conditions were also taken into account. Combining the bioinformatic mining results and RT-qPCR and Western blotting validations, we present some new insights into the molecular mechanisms explaining the HFF-metabolic adaption, and consequently provide a potential novel avenue for alleviating obesity and associated hepatic steatosis and insulin resistance.