Adipose tissue ketone bodies

Figure 27-1. Metabolic interrelationships between adipose tissue, the liver, and extrahepatic tissues. In extrahepatic tissues such as heart, metabolic fuels are oxidized in the following order of preference (1) ketone bodies, (2) fatty acids, (3) glucose. (LPL, lipoprotein lipase FFA, free fatty acids VLDL, very low density lipoproteins.)...

Adipose tissue releases free fatty acids in statvation, and these ate used by many tissues as fuel. Futthet-mote, in the hvet they ate the substtate fot synthesis of ketone bodies. 

Starvation elicits mobilization of triglycerides from the adipose tissue and inhibits the endogenic cholesterol synthesis owing to the low activity of hydroxy-methylglutaryl-CoA reductase. The latter process provides the possibility for the active production of ketone bodies in the liver. 

The physiological pathway for oxidation of ketone bodies starts with the hydrolysis of triacylglycerol in adipose tissue, which provides fatty acids that are taken up by the liver, oxidised to acetyl-CoAby P-oxidation and the acetyl-CoA is converted to ketone bodies, via the synthetic part of the pathway. Both hydroxybutyrate and acetoacetate are taken up by the tissues, which can oxidise them to generate ATP (Figure 7.19). 

Figure 7.19 The physiological pathway for ketone body oxidation from triacylglycerol in adipose tissue to their oxidation in a variety of tissues/organs. The pathway spans three tissues/ organs. The flux-generating step is the triacylglycerol lipase and ends with CO2 in one or more of the tissues/organs.

Figure 7.21 Provision of the fat fueb for the brain during hypo-glycaemia. During hypoglycaemia it is essential that ketone bodies are available for the brain to provide a fat fuel for ATP generation to maintain mental functions. This sequence of processes from adipose tissue to the brain is therefore, a survival pathway especially for children during short-term starvation or hypoglycaemia. (Box 7.2) (Chapter 16).

Ketone bodies are produced in the liver by partial oxidation of long-chain fatty acids arising from the triacylglyc-erol stored in adipose tissue, so that the question arises, why should one lipid fuel be converted into another There are several reasons. 

The ketone bodies are provided from fatty acids mobilised from adipose tissue. 

The liver is the most important site for the formation of fatty acids, fats (triacylglycewls), ketone bodies, and cholesterol. Most of these products are released into the blood, in contrast, the triacylglycerols synthesized in adipose tissue are also stored there. 

In the absence of insulin and in response to glucagon stimulation, triacylglycerol degradation in adipose tissue runs unabated and the flood of fatty acids reaching the liver leads to ketone body synthesis and packaging of some triacylglycerols into VLDLs. 

Individuals on very low-calorie diets, using the fats stored in adipose tissue as their major energy source, also have increased levels of ketone bodies in their blood and urine. These levels must be monitored to avoid the dangers of acidosis and ketosis (ketoacidosis). ... 

Skeletal muscle can use free fatty acids, ketone bodies, or glucose as fuel, depending on the degree of muscular activity (Fig. 23-17). In resting muscle, the primary fuels are free fatty acids from adipose tissue and... 

The liver converts fatty acids to triacyiglycerols, phospholipids, or cholesterol and its esters, for transport as plasma lipoproteins to adipose tissue for storage. Fatty acids can also be oxidized to yield ATP or to form ketone bodies, which are circulated to other tissues. 

Individuals with either type of diabetes are unable to take up glucose efficiently from the blood recall that insulin triggers the movement of GLUT4 glucose transporters to the plasma membrane of muscle and adipose tissue (see Fig. 12-8). Another characteristic metabolic change in diabetes is excessive but incomplete oxidation of fatty acids in the liver. The acetyl-CoA produced by JS oxidation cannot be completely oxidized by the citric acid cycle, because the high [NADH]/[NAD+] ratio produced by JS oxidation inhibits the cycle (recall that three steps convert NAD+ to NADH). Accumulation of acetyl-CoA leads to overproduction of the ketone bodies acetoacetate and /3-hydroxybutyrate, which cannot be used by extrahepatic tissues as fast as they are made in the liver. In addition to /3-hydroxybutyrate and acetoacetate, the blood of diabetics also contains acetone, which results from the spontaneous decarboxylation of acetoacetate ... 

During a fast, the liver is flooded with fatty acids mobilized from adipose tissue. The resulting elevated hepatic acetyl CoA produced primarily by fatty acid degradation inhibits pyruvate dehydrogenase (see p. 108), and activates pyruvate carboxylase (see p. 117). The oxaloacetate thus produced is used by the liver for gluconeogenesis rather than for the TCA cycle. Therefore, acetyl Co A is channeled into ketone body synthesis. 

Effects on lipid metabolism Glucagon favors hepatic oxidation of fatty acids and the subsequent formation of ketone bodies fan acetyl CoA. The lipolytic effect of glucagon in adipose tissue is minimal in humans. 

Which one of the following is characteristic of low insulin levels A. Increased glycogen synthesis B. Decreased gluconeogenesis from lactate C. Decreased glycogenolysis D. Increased formation of 3-hydroxybutyrate E. Decreased action of hormone-sensitive lipase Correct answer = D. 3-hydroxybutyrate—a ketone body—synthesis is enhanced in the liver by taw insulin levels, which favor activation of hormone-sensitive lipase and release of fatty acids from adipose tissue. Glycogen synthesis is decreased, whereas gluconeogenesis is increased. 

Because insulin normally inhibits lipolysis, a diabetic has an extensive lipolytic activity in the adipose tissue. As is seen in Table 21.4, plasma fatty acid concentrations become remarkably high. /3-Oxidation activity in the liver increases because of a low insulin/glucagon ratio, acetyl-CoA carboxylase is relatively inactive and acyl-CoA-camitine acyltransferase is derepressed. /3-Oxidation produces acetyl-CoA which in turn generates ketone bodies. Ketosis is perhaps the most prominent feature of diabetes mellitus. Table 21.5 compares ketone body production and utilization in fasting and in diabetic individuals. It may be seen that, whereas in the fasting state ketone body production is roughly equal to excretion plus utilization, in diabetes this is not so. Ketone bodies therefore accumulate in diabetic blood. 

---