Starvation, ketone bodies

Fatty acids do not serve as fuel for the brain, because they are bound to albumin in plasma and so do not traverse the blood-brain barrier. In starvation, ketone bodies generated by the liver partly replace glucose as fuel for the brain. 

The metabolic adaptations in starvation serve to minimize protein degradation. Large amounts of ketone bodies are formed by the liver from fatty acids and released into the blood within a few days after the onset of starvation. After several weeks of starvation, ketone bodies become the major fuel of the brain. The diminished need for glucose decreases the rate of muscle breakdown, and so the likelihood of survival is enhanced. 

During starvation, ketone bodies in the blood increase to a level that permits entry into brain cells, where they are oxidized. 

The liver is the only organ that can produce ketone bodies, yet it is one of the few that cannot use these molecules for energy production. Ketone bodies are produced when the rate of glucose synthesis is limited (i.e., substrates for gluconeogenesis are limited), and fatty acid oxidation is occurring rapidly. Ketone bodies can cross the blood-brain barrier and become a major fuel for the nervous system under conditions of starvation. Ketone body synthesis and metabolism have been described in Chapter 23. 

Ketone bodies provide important alternative fuels to body tissues when carbohydrate is in short supply or cannot be efficiently utilized. A particular example is the central nervous systems which cannot utilize plasma fatty acids for energy. Thus in prolonged starvation, ketone bodies become more important than glusose as a fuel source. The possibility of the utilization of ketone bodies obviates the harmful degradation of muscle protein for gluconeogenesis. In addition, acetoacetate and 3-hydroxybutyrate are thought to be important precursors for lipid synthesis in neonatal brain (Webber and Edmond, 1979). 

The primary fate of acetyl CoA under normal metabolic conditions is degradation in the citric acid cycle to yield C02. When the body is stressed by prolonged starvation, however, acetyl CoA is converted into compounds called ketone bodies, which can be used by the brain as a temporary fuel. Fill in the missing information indicated by the four question marks in the following biochemical pathway for the synthesis of ketone bodies from acetyl CoA ... 

In the liver, it forms ketone bodies (acetone, ace-toacetate, and 3-hydroxybutyrate) that are important fuels in prolonged starvation. 

Inherited aldolase A deficiency and pyruvate kinase deficiency in erythrocytes cause hemolytic anemia. The exercise capacity of patients with muscle phos-phofiaictokinase deficiency is low, particularly on high-carbohydrate diets. By providing an alternative lipid fuel, eg, during starvation, when blood free fatty acids and ketone bodies are increased, work capacity is improved. 

Increased fatty acid oxidation is a characteristic of starvation and of diabetes meUims, leading to ketone body production by the Ever (ketosis). Ketone bodies are acidic and when produced in excess over long periods, as in diabetes, cause ketoacidosis, which is ultimately fatal. Because gluconeogenesis is dependent upon fatty acid oxidation, any impairment in fatty acid oxidation leads to hypoglycemia. This occurs in various states of carnitine deficiency or deficiency of essential enzymes in fatty acid oxidation, eg, carnitine palmitoyltransferase, or inhibition of fatty acid oxidation by poisons, eg, hypoglycin. 

There is a small fall in plasma glucose upon starvation, then little change as starvation progresses (Table 27-2 Figure 27-2). Plasma free fatty acids increase with onset of starvation but then plateau. There is an initial delay in ketone body production, but as starvation progresses the plasma concentration of ketone bodies increases markedly. 

Brain Coordination of the nervous system Glycolysis, amino acid metabolism Glucose, amino acid, ketone bodies (in starvation) Polyunsaturated fatty acids in neonate Lactate ... 

In starvation, glucose must be ptovided for the brain and erythrocytes initially, this is supphed from hver glycogen reserves. To spare glucose, muscle and other tissues reduce glucose uptake in response to lowered insuhn secretion they also oxidize fatty acids and ketone bodies preferentially to glucose. 

Skeletal muscle can utilize ketone bodies during starvation. 

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. 

Brain Brain does not burn fat as an energy source however, after adapting to long-term starvation, brain can use ketone bodies for fuel. 

Many tissues (muscle, liver, renal cortex) prefer fat for an energy supply, at least in the resting state. The exception is red blood cells and brain. These tissues depend heavily on glycolysis for energy. Red cells cannot survive without glucose (no mitochondria), but during prolonged starvation, brain can adapt to utilize fat metabolites produced by the liver (ketone bodies). 

Brain, which is usually very reliant on glucose for energy, adapts in a few days of starvation to use ketone bodies as a source of energy. This spares the body some glucose, which is still essential to maintain red cell function. 

KETONE BODIES are generated by the liver and used by muscle and brain (after adaptation during starvation). 

Figure 3.18 Oxidation of glucose and ketone bodies by the brain. Glucose is the sole fuel used by the brain, except in prolonged starvation in adults or relatively short-term starvation in children. In both cases, ketone bodies plus glucose are used.

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