Glucosefatty Acid Cycle

The self-regulating interplay between glucose and fatty acid metabolism is called the glucose-fatty acid cycle. This cycle constitutes an important biochemical mechanism for limiting glucose utilization when alternative substrate is available, and conversely limiting the consumption of stored fat when glucose is available. Fatty acids that are produced in adipose tissue in an ongoing cycle of lipolysis and reesterification may either escape from fat cells to become the free fatty acids, or they may be retained as triglycerides, depending on the availability of «-glycerol phosphate (Fig. 1). The only source of «-glycerol phosphate for reesterification of fatty acids is the pool of triose phosphates derived from glucose oxidation, because adipose tissue is deficient in the enzyme required to phosphorylate and hence reuse glycerol released from triglycerides. Consequently, when glucose is abundant, «-glycerol phosphate is readily available, the rate of reesterification is high relative to lipolysis, and the rate of release of FFA is low. Conversely, when glucose is scarce, more fatty acids escape and plasma concentrations of FFA increase.

Exposure of muscle to elevated levels of FFA for several hours decreases transport of glucose across the plasma membrane and phosphorylation to glucose-6-phosphate. The resulting decrease of glucose-6-phos-phate, which is both a substrate and an allosteric activator of glycogen synthase, results in decreased glycogen formation as well as decreased glucose oxidation by glycolysis. Glycolysis may be further curtailed by inhibition of phosphofructokinase. Oxidation of fatty acids or ketone bodies also limits the oxidation of pyruvate to acetyl CoA. Recall from Chapter 41 that long-chain fatty acids must be linked to carnitine to gain entry into mitochondria where they are oxidized. Activity of acylcarnitine transferase is increased by long-chain fatty acid coenzyme A (CoA) and inhibited by malonyl CoA whose formation is accelerated when glucose is plentiful. Oxidation of long-chain fatty acids or ketone bodies to acetyl CoA reduces the cofactor nicotinamide-adenine dinucleotide (NAD) to NADH at a rate that exceeds oxidative regeneration in the nonworking muscle. The resulting scarcity of NAD and free CoA limits the breakdown of pyruvate directly, and also activates the mitochondrial enzyme pyruvate dehydrogenase (PDH) kinase that inactivates a key enzyme of pyruvate oxidation. The activity of PDH kinase, in turn, is inhibited by pyruvate.

Influx of fatty acids to the liver promotes ketogenesis and gluconeogenesis largely by the same mechanisms that diminish glucose metabolism in muscle. Metabolism of long-chain fatty acids inhibits the intramitochondrial oxidation of pyruvate to acetyl CoA. Gluconeogenic precursors arriving at the liver in the form of pyruvate, lactate, alanine, or glycerol are thus spared oxidation in the tricarboxylic acid cycle and instead are converted to phosphoenol pyruvate (PEP). Conversely, when glucose is abundant, the concentration of glucose-6-phosphate increases, and gluconeogenesis is inhibited both at the level of fructose-1,6-bisphosphate formation and at the level of pyruvate kinase (see Fig. 5 in Chapter 41). Under these circumstances malonyl CoA formation is increased and fatty acids are restrained from entering the mitochondria and subsequent degradation.

Through the reciprocal effects of glucose and fatty acids, glucose indirectly regulates its own rate of utilization by a negative feedback process that increases gluconeogenesis. Because of the intrinsic allosteric regulatory properties of the glucose-fatty acid cycle, hormones may regulate metabolic processes not only by altering the activities or amounts of enzymes, but also by influencing the flow of metabolites. The glucose-fatty acid cycle operates in normal physiology even though the concentration of glucose in blood remains nearly constant. In fact, the contribution of some hormones, notably gluco-corticoids and GH, to the maintenance of blood glucose and muscle glycogen depends in part on the glucose-fatty acid cycle. Conversely, in addition to stimulating glucose entry into muscle, insulin indirectly increases glucose metabolism by decreasing FFA mobilization from adipose tissue, thereby shutting down the inhibitory influence of the glucose-fatty acid cycle. This effect may be accelerated by a further effect of insulin to increase the formation of malonyl CoA in liver and muscle, thereby diminishing access of fatty acids to the mitochondrial oxidative apparatus.

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