Brain gluconeogenesis

Figure 16.11 Pattern of fuel utilisation during prolonged starvation. The major metabolic change during this period is that the rates of ketone body formation and their utilisation by the brain increases, indicated by the increased thickness of lines and arrows. Since less glucose is required by the brain, gluconeogenesis from amino acids is reduced so that protein degradation in muscle is decreased. Note thin line compared to that in Figure 16.9.

U (No CaM) < O Q. CL Heart, kidney, Brain, liver, widespread Cardiac function, Ca2+-dependent regulation, hormonal regulation of gluconeogenesis, cell proliferation, coincidence detector for NO... 

Central control of glucose homeostasis critically depends on the brain s ability to sense extracellular [glucose]. Within hypothalamus at least two types of neurons were identified which are presumably involved in this process. They are either glucose excited or glucose inhibited. Both types of neurons appear to be involved in the control of feeding, hepatic gluconeogenesis,... 

Cortisol-induced lipolysis not only provides substrates for gluconeogenesis (formation of glucose from noncarbohydrate sources) but it also increases the amount of free fatty acids in the blood. As a result, the fatty acids are used by muscle as a source of energy and glucose is spared for the brain to use to form energy. 

Answer C. Insulin increases glucose transport in only two tissues, adipose and muscle. The major site of glucose uptake is muscle, which decreases hyperglycemia. Glucose and ketone transport and metabolism are insulin independent in the brain (choice D). Insulin would slow gluconeogenesis (choice A) and fatty acid release from adipose (choice B). Insulin would inhibit glycogenolysis in the liver (choice E). 

In the brain, when ketones are metabolized to acetyl CoA, pyruvate dehydrogenase is inhibited. Glycolysis and subsequently glucose uptake in brain decreases. This important switch spares body protein (which otherwise would be catabolized to form glucose by gluconeogenesis in the liver) by allowing the brain to indirectly metabolize fetty acids as ketone bodies. 

Answer C. Glycogen depleted around 18 hours, gluconeogenesis from protein begins to drop gradually, and by two weeks, ketones have become the more important fuel for the brain. 

The situation is, however, different in starvation. In this condition, it is the degradation of muscle protein that provides the amino acids for gluconeo-genesis, so that all the oxo-acids generated (except those for lysine and lencine) are nsed to synthesise the glucose required for oxidation by the brain. Hence, a process other than amino acid oxidation mnst generate the ATP required by gluconeogenesis. This process is fatty acid oxidation. 

If starvation lasts for more than 24 hours, the rate of degradation of body protein (process 2) exceeds the rate of protein synthesis (process 3). The resultant amino acids are converted to oxoacids, most of which are converted to glucose (process 6) which is released and used predominantly by the brain (see Chapter 6). In this condition, the ATP required for gluconeogenesis is obtained from the oxidation of fatty acids (Figure 8.14(b)). 

An enhanced rate of hepatic gluconeogenesis to maintain the blood glucose level and provide the fuel for the brain and other tissues (Figure 16.9). 

Since much less glucose is required by the brain, the rate of gluconeogenesis falls and hence the rate of protein degradation falls. In the obese, the energy provided from the oxidation of glncose that has been provided by amino acids from protein degradation is as little as 5% of the total (it is much higher in the lean see below). 

Dnring starvation there is a decrease in the resting energy expenditnre which is due to reduced metabolic activity in most tissnes including, perhaps surprisingly, the brain. The decrease in muscle protein breakdown may, therefore, be a simple consequence of a decrease in the rate of glucose oxidation, so that gluconeogenesis from the amino acids is decreased. 

During periods of hunger, muscle proteins serve as an energy reserve for the body. They are broken down into amino acids, which are transported to the liver. In the liver, the carbon skeletons of the amino acids are converted into intermediates in the tricarboxylic acid cycle or into acetoacetyl-CoA (see p. 175). These amphibolic metabolites are then available to the energy metabolism and for gluconeogenesis. After prolonged starvation, the brain switches to using ketone bodies in order to save muscle protein (see p. 356). 

During periods of starvation, the brain after a certain time acquires the ability to use ketone bodies (see p. 312) in addition to glucose to form ATP. In the first weeks of a starvation period, there is a strong increase in the activities of the enzymes required for this in the brain. The degradation of ketone bodies in the CNS saves glucose and thereby reduces the breakdown of muscle protein that maintains gluconeogenesis in the liver during starvation. After a few weeks, the extent of muscle breakdown therefore declines to one-third of the initial value. 

Reduction of oxaioacetate synthesis aiso impairs gluconeogenesis, which compromises tissues dependent on glucose metabolism (such as the brain) during fasting. 

The net results of these actions are most apparent in the fasting state, when the supply of glucose from gluconeogenesis, the release of amino acids from muscle catabolism, the inhibition of peripheral glucose uptake, and the stimulation of lipolysis all contribute to maintenance of an adequate glucose supply to the brain. 

This Mg2+-activated enzyme is found on the lumenal side of the endoplasmic reticulum of hepatocytes and renal cells (see Fig. 15-6). Muscle and brain tissue do not contain this enzyme and so cannot carry out gluconeogenesis. Glucose produced by gluconeogenesis in the liver or kidney or ingested in the diet is delivered to brain and muscle through the bloodstream. 

In mammals, gluconeogenesis in the liver and kidney provides glucose for use by the brain, muscles, and erythrocytes. 

Under all these metabolic conditions, amino acids lose their amino groups to form a-keto acids, the carbon skeletons of amino acids. The a-keto acids undergo oxidation to C02 and H20 or, often more importantly, provide three- and four-carbon units that can be converted by gluconeogenesis into glucose, the fuel for brain, skeletal muscle, and other tissues. 

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