Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome

Abstract

Carbohydrates with high glycemic index are proposed to promote the development of obesity, insulin resistance and fatty liver, but the mechanism by which this occurs remains unknown. High serum glucose concentrations glucose are known to induce the polyol pathway and increase fructose generation in the liver. Here we show that this hepatic, endogenously-produced fructose causes systemic metabolic changes. We demonstrate that mice unable to metabolize fructose are protected from an increase in energy intake and body weight, visceral obesity, fatty liver, elevated insulin levels and hyperleptinemia after exposure to 10% glucose for 14 weeks. In normal mice, glucose consumption is accompanied by aldose reductase and polyol pathway activation in steatotic areas. In this regard, we show that aldose reductase deficient mice were protected against glucose-induced fatty liver. We conclude that endogenous fructose generation and metabolism in the liver represents an important mechanism whereby glucose promotes the development of metabolic syndrome.

Adiponectin Resistance and Proinflammatory Changes in the Visceral Adipose Tissue Induced by Fructose Consumption via Ketohexokinase-Dependent Pathway

“…1A), which was not observed in KHK-A/C-KO mice. The effect of KHK might be dependent on the pool of glucose converted to more lipogenic fructose in the liver, as shown recently (26). On the other hand, glucose feeding did not cause insulin resistance (Supplementary Fig.…”

Fructose metabolism and metabolic disease

“…Whether endogenous fructose synthesis might occur at sufficient rates to contribute to other aspects of fructose-induced cardiometabolic risk has only recently been addressed. Glucose dose-dependently induces aldolase reductase in human tissues, and chronic exposure to a high-glucose diet induces polyol pathway activation in mice (99,111). This may be a mechanism by which severe hyperglycemia may exacerbate cardiometabolic risks.…”

“…These mice fail to thrive and die when exposed to highfructose diets. Interestingly, even on a fructose-free diet, Aldobdeficient mice develop steatosis (98), possibly due to impaired metabolism of endogenously synthesized fructose (99).…”

New Insights on the Risk for Cardiovascular Disease in African Americans

“…Even the ability of non-fructose-containing carbohydrates to cause fatty liver and hyperinsulinemia can be prevented by blocking fructose metabolism, as some of the carbohydrates are converted to fructose in the liver after ingestion. 118 Studies in humans have also shown the remarkable ability of fructose to induce features of metabolic syndrome. [119][120][121] While some clinical studies have argued that fructose is not special in its ability to induce metabolic syndrome, [122][123][124] these latter studies inevitably are short term or have defects in experimental design (discussed by Johnson et al 107 ).…”

“…[132][133][134] One of the consequences of the studies on fructose metabolism is the recognition that it is not the caloric content that matters as much as whether ATP depletion occurs, the latter being primarily governed by the concentration of fructose that hits the liver. 108,118,135 This provides strong reasoning why soft drinks and sugary beverages may be so tightly associated with the development of obesity, metabolic syndrome, diabetes, and cardiovascular disease, 132,[136][137][138][139][140][141][142][143][144][145][146][147][148][149] as sugary beverages are often highly concentrated in fructose and are frequently ingested rapidly.…”