Hormonal Regulation of Fuel Metabolism: - During Fasting and Starvation, Metabolism Shifts to Provide Fuel for the Brain
The fuel reserves of a healthy adult human are of three types: glycogen stored in the liver and, in relatively small quantities, in muscles; large quantities of triacylglycerols in adipose tissues; and tissue proteins, which can be de graded when necessary to provide fuel (Table 23–5). In the first few hours after a meal, the blood glucose level is diminished slightly, and tissues receive glucose released from liver glycogen. There is little or no syn thesis of lipids. By 24 hours after a meal, blood glucose has fallen further, insulin secretion has slowed, and glucagon secretion has increased. These hormonal signals mobilize triacylglycerols, which now become the primary fuel for muscle and liver. Figure 1 shows the responses to prolonged fasting. 1 To provide glucose for the brain, the liver degrades certain proteins—those most expendable in an organism not ingesting food. Their nonessential amino acids are transaminated or deaminated , and 2 the extra amino groups are converted to urea, which is exported via the bloodstream to the kidney and excreted. Also in the liver, 3 the carbon skeletons of glucogenic amino acids are converted to pyruvate or inter mediates of the citric acid cycle. 4 These intermediates, as well as the glycerol 5 derived from triacyl glycerols in adipose tissue, provide the starting materials for gluconeogenesis in the liver, yielding glucose for the brain. Eventually the use of citric acid cycle inter mediates for gluconeogenesis depletes oxaloacetate, inhibiting entry of acetyl-CoA into the citric acid cycle. 6 Acetyl-CoA produced by fatty acid oxidation now accumulates, favoring 7 the formation of acetoacetyl-CoA and ketone bodies in the liver. After a few days of fasting, the levels of ketone bodies in the blood rise (Fig. 2) as these fuels are exported from the liver to the heart, skeletal muscle, and brain, which use them instead of glucose (8). Acetyl-CoA is a critical regulator of the fate of pyruvate; it allosterically inhibits pyruvate dehydrogenase and stimulates pyruvate carboxylase . In these ways acetyl-CoA prevents it own further pro duction from pyruvate while stimulating the conversion of pyruvate to oxaloacetate, the first step in gluconeogenesis.
Triacylglycerols stored in the adipose tissue of a normal-weight adult could provide enough fuel to maintain a basal rate of metabolism for about three months; a very obese adult has enough stored fuel to endure a fast of more than a year (Table 23–5). When fat reserves are gone, the degradation of essential proteins begins; this leads to loss of heart and liver function, and even tually death. Stored fat can provide adequate energy (calories) during a fast or rigid diet, but vitamins and minerals must be provided, and sufficient dietary glucogenic amino acids are needed to replace those being used for gluconeogenesis. Rations for those on a weight reduction diet are therefore commonly fortified with vitamins, minerals, and amino acids or proteins.
FIGURE 1 Fuel metabolism in the liver during prolonged fasting or in uncontrolled diabetes mellitus. After depletion of stored carbohydrates, 1 to 4 proteins become an important source of glucose, produced from glucogenic amino acids by gluconeogenesis. 5 to 8 Fatty acids imported from adipose tissue are converted to ketone bodies for export to the brain. Broken arrows represent reactions with reduced flux under these conditions. The steps are further described in the text.
FIGURE 2 Concentrations of fatty acids, glucose, and ketone bodies in the plasma during the first week of starvation. Despite the hormonal mechanisms for maintaining the level of glucose in the blood, it begins to diminish after two days of fasting. The level of ke tone bodies, almost immeasurable before the fast, rises dramatically after 2 to 4 days of fasting. These water-soluble ketones, acetoacetate and -hydroxybutyrate, supplement glucose as an energy source during a long fast. Fatty acids cannot serve as a fuel for the brain; they do not cross the blood-brain barrier.
