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Diets high in sucrose or in high-fructose syrups (HFS) used in manufactured foods and beverages lead to large amounts of fructose (and glucose) entering the hepatic portal vein. Excessive fructose intake (>50g/d) has been found to be one of the underlying etiologies of obesity, insulin resistance and metabolic syndrome.

Much of the ingested fructose is metabolized by the liver, using the fructose 1-phosphate pathway (See figure) .The first step is the phosphorylation of fructose to fructose 1-phosphate by fructokinase. Fructose-1-phosphate is then split into glyceraldehyde and Dihydroxyacetone phosphate, an intermediate in glycolysis. Since there is only one phosphate attached to Fructose, it goes to only one of the trioses, the other is subsequently phosphorylated. This aldol cleavage is catalyzed by a specific fructose 1-phosphate aldolase. Glyceraldehyde is then phosphorylated to glyceraldehyde-3-phosphate, a glycolytic intermediate, by triose kinase. Alternatively, fructose can be phosphorylated to fructose 6-phosphate by hexokinase. The two triose phosphates, Dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, may be degraded by glycolysis or may be substrates for aldolase and hence gluconeogenesis, which is the fate of much of the fructose metabolized in the liver. (See figure and follow the steps)

Fructose undergoes more rapid glycolysis in the liver than does glucose, because it   bypasses the regulatory step catalyzed by phosphofructokinase (Figure). This allows fructose to flood the pathways in the liver. High fructose consumption can lead to excess pyruvate production, causing  a build up of acetyl CoA which is directed toward fatty acid synthesis. Additionally, DHAP can be converted to glycerol-3-phosphate providing the glycerol backbone for the triglyceride molecule. Triglycerides are incorporated into very low density lipoproteins (VLDL), the carriers for transportation   of endogenously synthesized lipids , which are released from the liver destined toward peripheral tissues for storage in both fat and muscle cells. causing obesity. Excessive fructose consumption is also believed to contribute to the development of non-alcoholic fatty liver disease.

figure showing relationship of excessive consumption of fructose with obesity (GA- Glyceraldehyde,GA-3-P Glyceraldehyde-3-9, G-3-P- Glycerol-3 phosphate, DHAP- Dihydroxyacetone phosphate
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One Response to Consumption of high-fructose diets can cause obesity

  • The metabolism of fructose differs from that of glucose in several ways. Glucose enters cells by a transport mechanism (Glut-4) that is insulin dependent in most tissues (Adipose tissues and skeletal muscles). Insulin activates the insulin receptor, which in turn increases the density of glucose transporters on the cell surface and thus facilitates the entry of glucose. Once inside the cell, glucose is phosphorylated by glucokinase/hexokinase to become glucose-6-phosphate, from which the intracellular metabolism of glucose begins. Intracellular enzymes can tightly control conversion of glucose-6-phosphate to the glycerol backbone of triacylglycerols through modulation by phosphofructokinase. In contrast with glucose, fructose enters cells via a Glut-5 transporter that does not depend on insulin. This transporter is absent from pancreatic ß cells and the brain, which indicates limited entry of fructose into these tissues. Glucose provides “satiety” signals to the brain that fructose cannot provide because it is not transported into the brain. Once inside the cell, fructose is phosphorylated to form fructose-1-phosphate. In this configuration, fructose is readily cleaved by aldolase to form trioses that are the backbone for phospholipid and Triacylglycerol synthesis.Thus, fructose facilitates the biochemical formation of triacylglycerols more efficiently than does glucose.