Evidence suggests that dietary fructose is involved in the development of obesity. Physiologically, fructose is absorbed and metabolised in a way that lends itself towards the synthesis of fatty acids and the development of insulin resistance. However, the metabolic fate of fructose is determined to a large extent by the quantity of fructose consumed. Small amounts of fructose from natural sources (like fruit) in a normal mixed diet are unlikely to be problematic. However, diets high in sugar, and high fructose corn syrup (HFCS) have the potential to produce deleterious metabolic consequences to the individual. The metabolic abnormalities caused by fructose infusion are known, but it is not clear whether high concentrations of fructose in the diet can replicate these condition. If this is the case, then fructose ingestion may lead to long term-term metabolic dysfunction that results in disease.
Sources of fructose include sweeteners such as HFCS, as well as natural fructose in fruit. Sucrose can be present artificially as a sweetener or naturally in some fruits. Sucrose is a disaccharide and contains a molecule of glucose and a molecule of fructose bound by a glycosidic bond. During digestion this bond is hydrolysed to release the monosaccharide sugars. Fructose absorption begins in the jejunum by non-sodium dependent facilitated diffusion. In contrast, glucose is absorbed in the duodenum by the sodium glucose transporter. The consequence of this for fructose is a relatively slow rate of absorption and an inability to be absorbed against a concentration gradient. Evidence for the facilitated diffusion of fructose comes from data showing that the structurally similar phlorrhizin is able to slow the rate of galactose but not fructose, which suggests a separate carrier for fructose that is not used by glucose, galactose or phlorrhizin.
Ingested glucose stimulates the release of insulin from the pancreas, however fructose does not. Evidence suggests that this is because the β-cells of the pancreas do not possess the glut-5 transporter. This is important because insulin is able to regulate food intake by two known mechanisms. Firstly, insulin directly influences the central nervous system and induce satiety. Secondly, insulin stimulates the release of leptin from adipocytes through insulin induced changes in the glucose metabolism. Leptin is known to be inversely associated with body fat stores and inhibits release of the orexic hormones neuropeptide Y (NPY) and agouti-related peptide (AgRP), and stimulate the release of the anorexic hormones pro‑opiomelanocortin and adrenocorticotropin hormone. Because fructose does not cause the secretion of insulin, it by-passes these appetite regulating steps and this may have consequences on food intakes and weight gain in the long-term.
Once absorbed, glucose enters liver and muscle cells via the glut-4 and glut-2 transporters, which are both dependent on insulin for their action. Insulin binds to the insulin receptor using chromium and a cofactor, and this causes an increase in the quantity of glucose transporters on the surface of the cell, which increases glucose uptake. Glucose transported into the cell is phosphorylated by hexokinase or glucokinase to form glucose 6-phosphate which can then enter glycoslysis. Glycolysis is tightly regulated through modulation of phosphofruktokinase-1, and this crucial step prevents the uncontrolled flux of glucose 6-phosphate to acetyl-CoA. In contrast, fructose enters the cell via the glut-5 transporter which is not dependent on insulin to function. Because the glut-5 transporter in not present in brain tissue, fructose is not taken up by the brain and cannot provide the same satiety signals as glucose.
As fructose enters the liver cell, it is phosphorylated to fructose 1-phosphate, and subsequently metabolised to glyceraldehyde 3-phosphate and dihydroacetone phosphate in a reaction catalysed by aldolase. These triose phosphates then feed into glycolysis, but they miss the phosphofructokinase-1 regulator step and so flux through the pathway is not tightly controlled as with glucose. This uncontrolled flux through glycolysis is suggested to increase fatty acid synthesis via the process of de novo lipogenesis, as acetyl-CoA undergoes conversion to malonyl-CoA and subsequently to palmitate. The conversion of fructose 1-phosphate to the triose phosphates provides the 3-carbon backbone for the subsequent esterification of the fatty acids to form triglycerides. Thus fructose facilitates the formation of fatty acids and triglycerides more readily that glucose. A diet containing 17% fructose increased plasma triglycerides by 32%, compared to a control. Raised plasma fatty acids concentrations may contribute to insulin resistance and inflammation.
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