Adipose tissue fatty acid esterification

Figure 16.3 Effects of insulin on the glucose/fatty acid cycle. Insulin enhances glucose metabolism by stimulating glucose uptake by muscle and adipose tissue and by inhibiting lipolysis in adipose tissue (see Chapter 12 for the mechanism of these effects). The effect of glucose metabolism on lipolysis is via stimulation of fatty acid esterification via glycerol 3-phosphate.

Enzyme systems in adipose tissue participating in fatty acid esterification. Bull. Res. 

In the fed state, in response to the action of insulin (section 10.5) lipoprotein lipase is active at the surface of cells in adipose tissue. It catalyses the hydrolysis of triacylglycerols in chylomicrons, and most of the resultant free fatty acid is taken up by adipose tissue for re-esterification to triacylglycerol for storage. The chylomicron remnants are taken up by the liver, by a process of receptor-mediated endocytosis (section 5.6.2), and most of the residual lipid is secreted, together with triacylglycerol synthesised in the liver, in very low-density lipoproteins (section 5.6.2.2). 

There is futile cycling of lipids. Hormone sensitive lipase in adipose tissue (section 10.5.1) is activated by a small proteoglycan produced by tumours that cause cachexia (but not by those that do not). This results in liberation of fatty acids from adipose tissue, and re-esterification to triacylglycerols (which are exported in VLDL section 5.6.2.2) in the liver. As discussed in section 5.6.1.2, esterification of fatty acids to triacylglycerol is an energy-expensive process. 

There is a continuous release of non-esterified fatty acids from adipose tissue. In the fed state most of the fatty acids are taken up by the liver, re-esterified to form triacylglycerol and exported in VLDL (section 5.6.2.2). This apparently futile (and ATP-expensive) cycling between lipolysis in adipose tissue and re-esterification in the liver permits increased utilization of fatty acids as fuel in muscle by increasing the rate of fatty acid uptake into muscle without the need to increase the rate of lipolysis. As discussed in section 10.6, the extent to which muscle utilizes fatty acids is determined to a considerable extent by the intensity of physical activity, rather than by their availability. 

Insulin stimulates lipogenesis by several other mechanisms as well as by increasing acetyl-CoA carboxylase activity. It increases the transport of glucose into the cell (eg, in adipose tissue), increasing the availability of both pyruvate for fatty acid synthesis and glycerol 3-phosphate for esterification of the newly formed fatty acids, and also converts the inactive form of pyruvate dehydrogenase to the active form in adipose tissue but not in liver. Insulin also—by its ability to depress the level of intracellular cAMP—inhibits lipolysis in adipose tissue and thereby reduces the concentration of... 

Adipose tissue Storage and breakdown of triacylglyc-erol Esterification of fatty acids and lipolysis lipogenesis Glucose, lipoprotein triacylglycerol Free fatty acids, glycerol Lipoprotein lipase, hormone-sensitive lipase... 

Figure 16.1 The glucose/fatty add cycle. The dotted Lines represent regulation. Glucose in adipose tissue produces glycerol 3-phosphate which enhances esterification of fatty acids, so that less are available for release. The effect is, therefore, tantamount to inhibition of lipolysis. Fatty acid oxidation inhibits pyruvate dehydrogenase, phosphofructokinase and glucose transport in muscle (Chapters 6 and 7) (Randle et al. 1963).

The release of fatty acids from adipose tissue is regulated by the rate of hydrolysis of triacylglycerol and the rate of esterification of acyl-CoA with glycerol 3-phosphate. The rate of hydrolysis is stimulated by hormones that bind to cell-surface receptors and stimulate adenylate cyclase (which catalyzes the production of cAMP from ATP). Hormone-sensitive lipase (Sec. 13.4) can exist in two forms, one of which exhibits very low activity and a second which is phosphorylated and has high activity. Before hormonal stimulation of adenylate cyclase, the low-activity lipase predominates in the fat cell. Stimulation of protein kinase by an increase in cAMP concentration leads to phosphorylation of the low-activity lipase. An increase in the rate of hydrolysis of triacylglycerol and the release of fatty acids from the fat cell follows. This leads to a greater utilization of fatty acids by tissues such as heart, skeletal muscle, and liver. 

The hepatic CTP activity was enhanced by treatment with both forms of CLA, whereas the microsomal phos-phatidate phosphohydrolase (PAP) activity in liver was reduced. Hence, the results indicate that CLA might induce P-oxidation rather than esterification of fatty acids into TAG. The increase in P-oxidation may ultimately prevent the storage of TAG in the liver and adipose tissues. 

Raben and Hollenberg (1959a, 1960) incubated e.pididymal adipose tissue from fed rats with oleic acid in an albumin-containing medium and determined the concentration of free fatty acid in the medium and in the tissue at the end of the incubation. The concentration of acid in the tissue at the end of the incubation was three or four times that in the medium, and there was usually a disappearance of some of the medium acid. The effect of glucose and insulin in vitro was to deerea.se, the concentration of free acid in the tissue and to reduce the total free fatty acid in the system (tissue plus medium) during incubation. The authors concluded that the effect of glucose and insulin was on the esterification of free fatty acids. 

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