Increased sugar consumption is considered to be a contributor to the worldwide epidemics of obesity and diabetes and the consequent cardio metabolic risks. These include a significant increase for Type II diabetes and associated multiple comorbidities such as non-alcoholic fatty liver disease (NAFLD). The accumulation of excess triglycerides characterizes NAFL with a prevalence of up to 53% in morbidly obese populations. While in itself benign, fatty liver can progress to non-alcoholic steatohepatitis (NASH), which is characterized by apoptosis, inflammation and fibrosis in 10-20% of individuals. Progression to NASH increases the risk of further deterioration to cirrhosis and hepatocellular carcinoma (HCC). However, progression is unpredictable in any given individual and no risk factors predisposing to progression have been identified. Variation in a limited number of genes, such as patatin-like phospholipase (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), have been linked to an increased susceptibility to NAFLD. Recently, fibroblast growth factor 21 (FGF21) was reported to be a potential predictor for NAFLD as it significantly increases in patients with obesity and NAFL. Multiple lines of evidence indicate that FGF21 plays an important role in liver metabolism in mice and humans, playing a key role in carbohydrate and lipid metabolism. FGF21 was originally identified as an endocrine member of the fibroblast growth factor family as it can be released into the circulation. FGF21 was initially assigned a purely metabolic role as infusions led to weight loss and increased glucose clearance through induced expression of the GLUT1 transporter. However, FGF21 biology is now understood to be extremely complex, as it is expressed in many metabolically active tissues including, liver, white (WAT) and brown adipose tissue (BAT), muscle and pancreas. Functions of FGF21 are distinct in all these tissues. In the previous studies from our lab, we have seen fructose consumption, but not glucose, leads to an increase in serum FGF21 levels both in humans and mice. In general, sugar is typically consumed by humans in the form of sucrose or high fructose corn syrup (HFCS), both of which consist of nearly equal amounts of the simple sugars, glucose and fructose. Although attention has been focused on sucrose and fructose in many studies, no direct comparison was found to study fructose, glucose and sucrose. The current study aims to expand on the role of FGF21 in mediating the effects of chronic consumption of these refined sugars in mice. Wildtype (WT) and FGF21 knockout (KO) mice were fed with one of these diets for 20 weeks and in general, mice eating diets with high refined sugars gained less weight than mice eating chow, although calorie consumption was the same. In terms of body composition, sucrose fed FGF21 KO mice had less fat mass compared to chow fed animals. Dextrose fed and fructose fed mice had comparable fat mass reduction in WT and KO mice. Interestingly, glucose tolerance tests (GTT) showed increased glucose sensitivity in dextrose fed WT and KO mice after four weeks, however glucose tolerance decayed after 12 weeks on the diet. At 16 weeks fructose fed KO mice had significant increased glucose sensitivity compared to controls. Insulin tolerance tests showed similar results between all cohorts and a larger sample size would be needed to elicit any differences. Pyruvate tolerance tests (PTT) showed significantly increased hepatic gluconeogenesis in fructose fed KO mice compared to controls but not in dextrose or sucrose fed mice. Energy expenditure was measured by indirect calorimetry. No significance changes were observed in dextrose fed mice compared to chow controls in terms of VO2 or heat production. Both WT and KO dextrose fed mice had a higher RER, consistent with utilization of carbohydrates over fat for baseline energy expenditure. Sucrose fed mice showed marked increases in VO2 over an averaged 24-hour period and similarly fructose fed mice FGF21 KO mice had increased energy expenditure. Significant increases in RER were observed in both WT and KO sucrose fed mice controls and a similar trend was observed in WT and KO fructose fed mice. Overall, we see differential metabolic effects of all the high carbohydrate diets on the mice. Chronic consumption of dextrose only affected glucose sensitivity. Whereas chronic consumption of sucrose influences glucose and insulin sensitivity and energy expenditure suggesting internal metabolic changes while fructose consumption additionally showed increased hepatic gluconeogenesis without the marked increase in insulin sensitivity. However, detailed tissue analysis is required to determine specific physiological and molecular changes between refined sugar cohorts and the role of FGF21 in this context.

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