23.3 Hormonal Regulation of Fuel Metabolism in Chapter 23 Hormonal Regulation and Integration of Mammalian Metabolism

Insulin Counters High Blood Glucose in the Well-Fed State

After a high-carbohydrate meal, blood glucose rises several-fold. In response, insulin is released and acts through its plasma membrane receptors in muscle and liver (see Figs. 12-22, 12-23) to stimulate glucose uptake, phosphorylation, and oxidation via glycolysis and the citric acid cycle (Table 23-3). In response to insulin, GLUT4 glucose transporters sequestered in intracellular vesicles move to the plasma membrane, dramatically increasing the uptake of glucose from the blood (see Box 11-1). In the liver, insulin activates glycogen synthase and inactivates glycogen phosphorylase, so that much of the glucose 6-phosphate derived from blood glucose is channeled into glycogen.

TABLE 23-3 Effects of Insulin on Blood Glucose: Uptake of Glucose by Cells and Storage as Triacylglycerols and Glycogen
Metabolic effect	Target enzyme
$↑$ $up-arrow$ Glucose uptake (muscle, adipose tissue)	$↑$ $up-arrow$ Glucose transporter (GLUT4)
$↑$ $up-arrow$ Glucose uptake (liver)	$↑$ $up-arrow$ Glucokinase (increased expression)
$↑$ $up-arrow$ Glycogen synthesis (liver, muscle)	$↑$ $up-arrow$ Glycogen synthase
$↓$ $down-arrow$ Glycogen breakdown (liver, muscle)	$↓$ $down-arrow$ Glycogen phosphorylase
$↑$ $up-arrow$ Glycolysis, acetyl-CoA production (liver, muscle)	$↑$ $up-arrow$ PFK-1 (by PFK-2) $↑$ $up-arrow$ Pyruvate dehydrogenase complex
$↑$ $up-arrow$ Fatty acid synthesis (liver)	$↑$ $up-arrow$ Acetyl-CoA carboxylase
$↑$ $up-arrow$ Triacylglycerol synthesis (adipose tissue)	$↑$ $up-arrow$ Lipoprotein lipase

Insulin also stimulates the storage of excess fuel as fat in adipose tissue (Fig. 23-22). Excess acetyl-CoA not needed for energy production via the citric acid cycle is used for fatty acid synthesis. These fatty acids are converted to TAGs in the liver and exported to adipose tissue as components of plasma lipoproteins (VLDL; see Fig. 21-40). In adipose tissue, TAGs are released from VLDL as fatty acids, which are taken up by adipocytes and reconverted to TAGs for storage in response to insulin stimulation.

A figure shows the process that takes place in the liver and other organs after a calorie-rich meal. — FIGURE 23-22 The well-fed state: the lipogenic liver. Immediately after a calorie-rich meal, glucose, fatty acids, and amino acids enter the liver. Blue arrows follow the path of glucose; orange arrows follow the path of lipids. Insulin released in response to the high blood glucose concentration stimulates glucose uptake by the tissues. Some glucose is exported to the brain for its energy needs, and some goes to adipose and muscle tissue. In the liver, excess glucose is oxidized to acetyl-CoA, which is used to make triacylglycerols for export to adipose and muscle tissue. The NADPH necessary for lipid synthesis is obtained by oxidation of glucose in the pentose phosphate pathway. Excess amino acids are converted to pyruvate and acetyl-CoA, which are also used for lipid synthesis. Dietary fats move from the intestine as chylomicrons, via the lymphatic system, to the liver, muscle, and adipose tissues.

The liver is shown as two roughly triangular lobes in the center of the illustration. The intestine is shown to the left as a vertical tube. From top to bottom, the intestine contains glucose, amino acids, and fats. An arrow points from fats in the intestine to a small, light yellow tube labeled lymphatic system that contains T A G. Two arrows point from the lymphatic system, one pointing to fatty acids in a fusiform muscle and one pointing to T A G in the liver. In muscle, an arrow points down from fatty acids with an arrow branching off to show the release of A T P within the muscle before yielding C O 2 shown outside of the muscle. The T A G that travels from the lymphatic system to the liver has a red arrow point right to V L D L outside of the liver. A black arrow points down from V L D L to fatty acids in the fusiform muscle below. A red arrow points from V L D L to T A G in adipose tissue to the right, shown as a narrow, roughly triangular structure made up of irregularly-shaped spheres. In the intestine, a black arrow points from amino acids through a red tubular blood vessel to amino acids in the liver and a thick blue arrow points from glucose through the same blood vessel to glucose in the liver. The pancreas is shown above as a tan organ with many small, roughly round pieces joined together to make a long piece across the top that narrows to the upper right and a wider left side that bends down and folds back toward the right. An arrow points up from the pancreas to the word insulin with short red lines radiating from all sides and accompanying text reading, to brain, adipose, muscle. A similar arrow points down to insulin with short red lines radiating from all sides, from which an arrow points to the liver at the point that glucose enters the liver. The amino acids that react the liver from the intestine have a curved arrow down to protein synthesis to the lower right and a short arrow down to alpha-keto acids plus N H 3. An arrow points right from N H 3 to urea and an arrow points right from alpha-keta acids to acetyl-Co A. A red arrow points down from acetyl-Co A to T A G from the lymphatic system an a blue arrow points right from acetyl-Co A with a branched arrow showing the loss of A T P to yield C O 2. Glucose that enters the liver from the intestine has a blue arrow pointing right to glycogen, a blue arrow pointing down to acetyl-CoA, and a blue arrow pointing up out of the liver to the word glucose again. From this glucose, outside of the liver, a black arrow points to the fusiform muscle, a black arrow points to the adipose tissue, and a blue arrow points to glucose in the brain. Glucose in the brain has an arrow pointing down that splits to yield A T P within the brain and C O 2 that leaves the brain.

In summary, an important effect of insulin is to bring about the conversion of excess blood glucose after a meal to two storage forms: glycogen (in the liver and muscle) and TAGs (in adipose tissue).

Pancreatic β Cells Secrete Insulin in Response to Changes in Blood Glucose

The peptide hormones insulin, glucagon, and somatostatin are produced by clusters of specialized pancreatic cells, the islets of Langerhans (Fig. 23-23). Each cell type of the islets produces a single hormone: α cells produce glucagon; β cells, insulin; and δ cells, somatostatin. When glucose enters the bloodstream from the intestine after a carbohydrate-rich meal, the resulting increase in blood glucose causes the pancreas to secrete insulin (and to decrease the secretion of glucagon).

A figure shows the endocrine system of the pancreas with a close-up showing the specific cells involved. — FIGURE 23-23 The endocrine system of the pancreas. The pancreas contains both exocrine cells (see Fig. 18-3b), which secrete digestive enzymes in the form of zymogens, and clusters of endocrine cells, the islets of Langerhans. The islets contain α, β, and δ cells (also known as A, B, and D cells, respectively), each cell type secreting a specific peptide hormone.

The pancreas is shown above as a tan organ with many small, roughly round pieces joined together to make a long piece across the top that narrows to the upper right and a wider left side that bends down and folds back toward the right. A long, tan tubular structure runs along its length with many branches above and below. A close-up shows individual cells. A roughly circular region of cells is surrounded by large, rounded cells. One of these larger cells is labeled exocrine cell. The roughly circular region is labeled Islet of Langerhans. Within the roughly circular region, there are several red structures that are round to oval in shape an are labeled blood vessels. Many of the cells are small and orange with visible nuclei. These are labeled beta cell (insulin). Tan cells, which are primarily located around the outer borders of the structure, are labeled alpha cell (glucagon). Blue cells are present that range greatly in size, with some being very small and almost triangular and others being larger and more round. These are present through the center region of beta cells and some are present along the boundary. These are labeled gamma cell (somatostatin).

As shown in Figure 23-24, when blood glucose rises, GLUT2 transporters carry glucose into the β cells, where it is immediately converted to glucose 6-phosphate by glucokinase and enters glycolysis. With the higher rate of glucose catabolism, [ATP] increases, causing ATP-gated $K^{+}$ $bold upper K Superscript bold plus$ channels in the plasma membrane to close. Reduced efflux of $K^{+}$ $upper K Superscript plus$ depolarizes the membrane. (Recall from Section 12.6 that exit of $K^{+}$ $upper K Superscript plus$ through an open $K^{+}$ $upper K Superscript plus$ channel hyperpolarizes the membrane; thus, closing the $K^{+}$ $upper K Superscript plus$ channel effectively depolarizes the membrane.) Membrane depolarization opens voltage-gated ${Ca}^{2}^{+}$ $Ca squared Superscript plus$ channels, and the resulting increase in cytosolic [ ${Ca}^{2}^{+}$ $Ca squared Superscript plus$ ] triggers the release of insulin by exocytosis. The brain integrates inputs on energy supply and demand, and signals from the parasympathetic and sympathetic nervous systems also affect (stimulate and inhibit, respectively) insulin release. A simple feedback loop limits hormone release: insulin lowers blood glucose by stimulating glucose uptake by the tissues; the reduced blood glucose is detected by the β cell as a diminished flux through the glucokinase reaction; this slows or stops the release of insulin. This feedback regulation holds blood glucose concentration nearly constant despite large fluctuations in dietary intake.

A figure shows the process by which glucose concentration influences insulin secretion by pancreatic beta cells. — FIGURE 23-24 Glucose regulation of insulin secretion by pancreatic β cells. When the blood glucose level is high, active metabolism of glucose in the β cell raises intracellular [ATP], closing $K^{+}$ $upper K Superscript plus$ channels in the plasma membrane and thus depolarizing the membrane. In response to this membrane depolarization, voltage-gated ${Ca}^{2}^{+}$ $Ca squared Superscript plus$ channels open, allowing ${Ca}^{2}^{+}$ $Ca squared Superscript plus$ to flow into the cell. ( ${Ca}^{2}^{+}$ $Ca squared Superscript plus$ is also released from the ER, in response to the initial elevation of $[{Ca}^{2}^{+}]$ $left-bracket Ca squared Superscript plus Baseline right-bracket$ in the cytosol.) Cytosolic $[{Ca}^{2}^{+}]$ $left-bracket Ca squared Superscript plus Baseline right-bracket$ is now high enough to trigger insulin release by exocytosis. The numbered processes are discussed in the text.

A pancreatic beta cell is shown with the region above labeled as extracellular space. A glucose transporter is shown embedded in the membrane at the upper left. It consists of two blue halves that are close together at the bottom and separate at the top with a roughly hexagonal opening visible where the two parts separate as they exit the membrane. This transporter is labeled glucose transporter G L U T 2. In step 1, glucose in the extracellular space enters the transporter and moves into the cell. An arrow points down labeled blue highlighted glucokinase (hexokinase Roman numeral 4). This yields glucose 6-phosphate. A series of three arrows point downward labeled glycolysis, citric acid cycle, and oxidative phosphorylation, respectively. This yields step 2, an increase in A T P concentration shown as [A T P] upward-pointing arrow symbol from which a dashed arrow points to a red “X” in a red circle next to a purple A T P-gated K plus channel with an arrow showing the movement of K plus from the inside of the cell to the outside of the cell. Above this channel, there is a small vertical piece of membrane with six plus symbols on the outside beneath V subscript m end subscript accompanied by six minus symbols lined up alongside inside the membrane. An arrow labeled 3 and depolarization points from K plus emerging from this channel to a green voltage-gated C a 2 plus channel near the bottom center of the membrane. An arrow shows the movement of C a 2 plus across the channel into the cell to step 4, shown as [C a 2 plus] upward-pointing arrow symbol. The nucleus is shown to the upper right with endoplasmic reticulum round it and extending down to the lower right.. An arrow points from the endoplasmic reticulum to the increase in calcium concentration labeled 4. An arrow points from this increase in calcium concentration to step 5, where six circles with red dots inside are labeled insulin in secretory granules and an additional two are shown fusing with the membrane to release red particles outside of the cell. This process is labeled insulin secretion.

The activity of ATP-gated $K^{+}$ $upper K Superscript plus$ channels is central to the regulation of insulin secretion by β cells. The channels are octamers of four identical Kir6.2 subunits and four identical SUR1 subunits (Fig. 23-25a) and are constructed along the same lines as the $K^{+}$ $upper K Superscript plus$ channels of bacteria and those of other eukaryotic cells (see Fig. 11-45). The four Kir6.2 subunits form a cone around the $K^{+}$ $upper K Superscript plus$ channel and function as the selectivity filter and ATP-gating mechanism (Fig. 23-25b). When [ATP] rises, indicating increased blood glucose, the $K^{+}$ $upper K Superscript plus$ channels close, thus depolarizing the plasma membrane and triggering insulin release as shown in Figure 23-24. The sulfonylurea drugs, oral medications used in the treatment of type 2 diabetes mellitus, bind to the SUR1 (sulfonylurea receptor) subunits of the $K^{+}$ $upper K Superscript plus$ channels, closing the channels and stimulating insulin release.

A figure shows the ATP-gated K plus channels in beta cells shown as a diagram in the plane of the membrane in part a and showing the structure of the K i r 6.2 portion of the channel in part b. — FIGURE 23-25 ATP-gated $K^{+}$ $bold upper K Superscript bold plus$ channels in β cells. (a) The ATP-gated channel, viewed in the plane of the membrane. The channel is formed by four identical Kir6.2 subunits, which are surrounded by four SUR1 (sulfonylurea receptor) subunits. The SUR1 subunits have binding sites for ADP and the drug diazoxide, both of which favor the open channel, and tolbutamide, a sulfonylurea drug that favors the closed channel. The Kir6.2 subunits constitute the channel, and they contain, on the cytosolic side, binding sites for ATP and phosphatidylinositol 4,5-bisphosphate $left-parenthesis PIP Subscript 2 Baseline right-parenthesis$ $left-parenthesis PIP Subscript 2 Baseline right-parenthesis$ , which favor the closed and the open channel, respectively. (b) The structure of the Kir6.2 portion of the channel, viewed in the plane of the membrane. For clarity, only two transmembrane domains and two cytosolic domains are shown. Three $K^{+}$ $upper K Superscript plus$ ions (green) are shown in the region of the selectivity filter. Mutation in certain amino acid residues (shown in red) leads to neonatal diabetes; mutation in others (shown in blue) leads to hyperinsulinism of infancy. This structure was obtained by mapping the known Kir6.2 sequence onto the crystal structures of a bacterial Kir channel (KirBac1.1) and the amino and carboxyl domains of another Kir protein, Kir3.1. [Data from (b) KirBac1.1: PDB ID 1P7B, A. Kuo et al., *Science* 300:1922, 2003; Kir3.1: PDB ID 1U4E, S. Pegan et al., *Nature Neurosci.* 8:279, 2005. Coordinates courtesy of Frances M. Ashcroft, Oxford University, used with permission of S. Haider and M. S. P. Sansom to re-create a model published in J. F. Antcliff et al., *EMBO J.* 24:229, 2005.]

FIGURE 23-25 ATP-gated $K^{+}$ $bold upper K Superscript bold plus$ channels in β cells. (a) The ATP-gated channel, viewed in the plane of the membrane. The channel is formed by four identical Kir6.2 subunits, which are surrounded by four SUR1 (sulfonylurea receptor) subunits. The SUR1 subunits have binding sites for ADP and the drug diazoxide, both of which favor the open channel, and tolbutamide, a sulfonylurea drug that favors the closed channel. The Kir6.2 subunits constitute the channel, and they contain, on the cytosolic side, binding sites for ATP and phosphatidylinositol 4,5-bisphosphate $left-parenthesis PIP Subscript 2 Baseline right-parenthesis$ $left-parenthesis PIP Subscript 2 Baseline right-parenthesis$ , which favor the closed and the open channel, respectively. (b) The structure of the Kir6.2 portion of the channel, viewed in the plane of the membrane. For clarity, only two transmembrane domains and two cytosolic domains are shown. Three $K^{+}$ $upper K Superscript plus$ ions (green) are shown in the region of the selectivity filter. Mutation in certain amino acid residues (shown in red) leads to neonatal diabetes; mutation in others (shown in blue) leads to hyperinsulinism of infancy. This structure was obtained by mapping the known Kir6.2 sequence onto the crystal structures of a bacterial Kir channel (KirBac1.1) and the amino and carboxyl domains of another Kir protein, Kir3.1. [Data from (b) KirBac1.1: PDB ID 1P7B, A. Kuo et al., *Science* 300:1922, 2003; Kir3.1: PDB ID 1U4E, S. Pegan et al., *Nature Neurosci.* 8:279, 2005. Coordinates courtesy of Frances M. Ashcroft, Oxford University, used with permission of S. Haider and M. S. P. Sansom to re-create a model published in J. F. Antcliff et al., *EMBO J.* 24:229, 2005.]

Part a shows a horizontal membrane with the area above labeled outside and the area below labeled inside. A structure extending across the center of the membrane has four tan components that are all wider toward the outside and narrower toward the inside, giving them each a triangular appearance from the top. One is labeled K i r 6.2. There is a square channel visible in the center and an arrow points from a green sphere labeled K plus below to a similar sphere above to show that K plus passes through this channel. Each side of this structure had a gray structure on the outside that is semicircular with the flat portion against the inner part of the channel. These are labeled S U R 1. A T P is shown with a dashed arrow to a red “X” in a red circle at the left-side boundary between the front K i r 6.2 and S U R 1. P I P 2 has a dashed arrow to a green triangle surrounded by a green circle at the right-side boundary between the front K i r 6.2 and S U R 1. Diazoxide outside of the cell has a dashed arrow to a green triangle in a green circle at the upper left of the left-hand S U R 1. Tolbutamide outside of the cell has a dashed arrow to a red “X” in a red circle at the upper right of the right-hand S U R 1. A D P inside of the cell has a dashed arrow to a green triangle enclosed in a green circle at the lower right side of the right-hand S U R 1. Part b shows a horizontal membrane with the area above labeled outside and the area below labeled inside. A cylindrical gray piece labeled S U R 1 on the left angles slightly to the lower left, then meets a smaller cylindrical gray piece labeled S U R 1 below that angles toward the right. A cylindrical gray piece labeled S U R 1 on the right angles slightly to the lower right, then meets a smaller cylindrical gray piece labeled S U R 1 below that angles toward the left. Between these gray structures, there are tan proteins with tan diagonal helices extending to the upper left and upper right in parts labeled K i r 6.2. Blue wireframe rings are visible near the opening of a vertical channel between these that contains three green spheres with an arrow pointing up to another green sphere above the structure and outside of the cell. Near the center of the structure, two small helices extend horizontally on each side with some red wireframe structures around them. There is a wider opening between the parts below with a green sphere visible inside, some pleated strands on each side, and yellow spheres in a roughly horizontal orientation representing A T P to the left and right at the widest part. There are more pleated strands below, then a helix extends down on each side alongside the small bottom S U R 1 piece on each side. A green K plus is shown below with an arrow showing that it is about to move upward through the channel.

Mutations in the ATP-gated $K^{+}$ $upper K Superscript plus$ channels of β cells are, fortunately, rare. Mutations in Kir6.2 that result in constantly open $K^{+}$ $upper K Superscript plus$ channels (red residues in Fig. 23-25b) lead to neonatal diabetes mellitus, with severe hyperglycemia that requires insulin therapy. Other mutations in Kir6.2 or SUR1 (blue residues in Fig. 23-25b) produce permanently closed $K^{+}$ $upper K Superscript plus$ channels and continuous release of insulin. If untreated, individuals with these mutations develop a condition in which excessive insulin causes severe hypoglycemia (low blood glucose) leading to irreversible brain damage. One effective treatment is surgical removal of part of the pancreas to reduce insulin production.

Glucagon Counters Low Blood Glucose

Several hours after the intake of dietary carbohydrate, blood glucose levels fall slightly because of the ongoing oxidation of glucose by the brain and other tissues. Lowered blood glucose triggers the pancreas to secrete glucagon and simultaneously decrease the release of insulin (Fig. 23-26).

A figure shows fuel metabolism in the liver when an individual experiences uncontrolled diabetes mellitus or prolonged fasting. — FIGURE 23-26 The fasting state: the glucogenic liver. After some hours without a meal, the liver becomes the principal source of glucose for the brain. Liver glycogen is broken down to glucose 1-phosphate, and this is converted to glucose 6-phosphate, then to free glucose, which is released into the bloodstream. Amino acids from the degradation of proteins in liver and muscle, and glycerol from the breakdown of TAGs in adipose tissue, are used for gluconeogenesis. The liver uses fatty acids as its principal fuel, and excess acetyl-CoA is converted to ketone bodies for export to other tissues; the brain is especially dependent on this fuel when glucose is in short supply (see Fig. 23-19). Blue arrows follow the path of glucose; orange arrows, the path of lipids; and purple arrows, the path of amino acids.

The liver is shown as a structure with two roughly triangular lobes. Step 1: A fusiform muscle is shown above text that reads, protein degradation yields glucogenic amino acids. A purple arrow points down to a purple box labeled amino acids within the liver. From this box, a green arrow points to N H 3 from which a green arrow points to a green box labeled urea. A green arrow points from urea to a box labeled 2, which reads, Urea is exported to the kidney and excrete d in urine. A green arrow points up to an illustration of a kidney. From the box labeled amino acids, a purple arrow points down to curve up three times to join the citric acid cycle at three different places. The citric acid circle is shown as a dashed curved arrow from oxaloacetate at the nine o’clock position to citrate at the three-o’clock position. A short arrow points from citrate to the four o’clock position, where a purple line from amino acids joins a fifth arrow. A sixth arrow that runs across the six o’clock position is also joined by a purple line from amino acids, Another arrow points from the six-o’clock to seven o’clock positions. An arrow from the seven o’clock position to oxaloacetate is also joined by a purple line from amino acids. A blue arrow points up from oxaloacetate to phosphoenopyruvate. A box labeled 3 reads, Citric acid cycle intermediate (oxaloacetate) is diverted to gluconeogenesis. A blue arrow points from phosphoenopyruvate, from which a blue arrow points up to glucose 6-phosphate. From glucose 6-phosphate, a blue arrow points upward accompanied by a curved arrow showing the low of P subscript i end subscript and then a blue box labeled glucose is produced. A blue arrow points up from glucose to a box labeled 4 that reads, Glucose is exported via the bloodstream to the brain. A blue arrow points from this box to the brain. Adipose tissue is shown to the upper right as a long, roughly triangular mass of spheres. A red arrow points down to a box labeled 5 that reads, Fatty acids (imported from adipose tissue) are oxidized as fuel, producing acetyl Co A. A red arrow points down to an orange box labeled fatty acids in the liver, from which an orange arrow points left to an orange box labeled acetyl-Co A. A dashed black line points down from acetyl-Co A to citrate in the citric acid cycle below and a red arrow points up to acetoacetyl-Co A. A box labeled 6 reads, Lack of oxaloacetate prevents acetyl-Co A entry into the citric acid cycle; acetyl-Co A accumulates. A box labeled 7 reads, Acetyl-Co A accumulation favors ketone body synthesis. An red arrow points up from acetoacetyl-Co A to a red box labeled ketone bodies, from which an arrow points up to a box labeled 8 that reads, Ketone bodies are exported via the bloodstream to the brain, which uses them as fuel. A red arrow points up and branches to point to the brain and to point to a box labeled 9 that reads, Excess ketone bodies end up in urine. A red arrow points from this box to the diagram of a kidney.

Glucagon causes an increase in blood glucose concentration in several ways (Table 23-4). Like epinephrine, it stimulates the net breakdown of liver glycogen by activating glycogen phosphorylase and inactivating glycogen synthase; both effects are the result of phosphorylation of the regulated enzymes, triggered by cAMP. Glucagon inhibits glucose breakdown by glycolysis in the liver and stimulates glucose synthesis by gluconeogenesis. Both effects result from lowering the concentration of fructose 2,6-bisphosphate, an allosteric inhibitor of the gluconeogenic enzyme fructose 1,6-bisphosphatase (FBPase-1) and an activator of the glycolytic enzyme phosphofructokinase-1. Recall that [fructose 2,6-bisphosphate] is ultimately controlled by a cAMP-dependent protein phosphorylation reaction (see Fig. 14-25). Glucagon also inhibits the glycolytic enzyme pyruvate kinase, by promoting its cAMP-dependent phosphorylation, thus blocking the conversion of phosphoenolpyruvate to pyruvate and preventing oxidation of pyruvate via the citric acid cycle (see Fig. 14-26). The resulting accumulation of phosphoenolpyruvate favors gluconeogenesis. This effect is augmented by glucagon’s stimulation of the synthesis of the gluconeogenic enzyme PEP carboxykinase. By stimulating glycogen breakdown, preventing glycolysis and promoting gluconeogenesis in hepatocytes, glucagon enables the liver to export glucose, restoring blood glucose to its normal level.

TABLE 23-4 Effects of Glucagon on Blood Glucose: Production and Release of Glucose by the Liver
Metabolic effect	Effect on glucose metabolism	Target enzyme
$↑$ $up-arrow$ Glycogen breakdown (liver)	Glycogen $\to$ $right-arrow$ glucose	$↑$ $up-arrow$ Glycogen phosphorylase
$↓$ $down-arrow$ Glycogen synthesis (liver)	Less glucose stored as glycogen	$↓$ $down-arrow$ Glycogen synthase
$↓$ $down-arrow$ Glycolysis (liver)	Less glucose used as fuel in liver	$↓$ $down-arrow$ PFK-1
$↑$ $up-arrow$ Gluconeogenesis (liver)		$↑$ $up-arrow$ FBPase-2 $↓$ $down-arrow$ Pyruvate kinase $↑$ $up-arrow$ PEP carboxykinase
$↑$ $up-arrow$ Fatty acid mobilization (adipose tissue)	Less glucose used as fuel by liver, muscle	$↑$ $up-arrow$ Hormone-sensitive lipase
		$↑$ $up-arrow$ PKA (perilipin–)
$↑$ $up-arrow$ Ketogenesis	Provides alternative to glucose as energy source for brain	$↓$ $down-arrow$ Acetyl-CoA carboxylase

Although its primary target is the liver, glucagon (like epinephrine) also affects adipose tissue, activating TAG breakdown by causing cAMP-dependent phosphorylation of perilipin and hormone-sensitive lipase. The activated lipase liberates free fatty acids, which are exported to the liver and other tissues as fuel, sparing glucose for the brain. The net effect of glucagon is therefore to stimulate glucose synthesis and release by the liver and to mobilize fatty acids from adipose tissue, to be used instead of glucose by tissues other than the brain. All these effects of glucagon are mediated by cAMP-dependent protein phosphorylation.

During Fasting and Starvation, Metabolism Shifts to Provide Fuel for the Brain

A healthy adult human has three types of fuel reserves: glycogen stored in the liver and, in smaller quantities, in muscles; large quantities of TAG in adipose tissues; and tissue proteins, which can be degraded when necessary to provide fuel (Table 23-5).

TABLE 23-5 Available Metabolic Fuels in a Normal-Weight, 70 kg Man and in an Obese, 140 kg Man at the Beginning of a Fast
Type of fuel	Weight (kg)	Caloric equivalent (thousands of kcal (kJ))	Estimated survival (months)^a
Normal-weight, 70 kg man
Triacylglycerols (adipose tissue)	15	140 (590)
Proteins (mainly muscle)	6	24 (100)
Glycogen (muscle, liver)	0.23	0.90 (3.8)
Circulating fuels (glucose, fatty acids, triacylglycerols, etc.)	0.023	0.10 (0.42)
Total		165 (690)	3
Obese, 140 kg man
Triacylglycerols (adipose tissue)	80	750 (3,100)
Proteins (mainly muscle)	8	32 (130)
Glycogen (muscle, liver)	0.23	0.92 (3.8)
Circulating fuels	0.025	0.11 (0.46)
Total		783 (3,200)	14

Two hours after a meal, the blood glucose level is diminished slightly, and tissues receive glucose released from liver glycogen. There is little or no synthesis of TAGs. By four hours after a meal, blood glucose has fallen further, insulin secretion has slowed, and glucagon secretion has increased. These hormonal signals mobilize TAGs from adipose tissue, which now become the primary fuel for muscle and liver. Figure 23-27 shows the responses to prolonged fasting. 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 (Chapter 18), and the extra amino groups are converted to urea, which is exported via the bloodstream to the kidneys and excreted in the urine.

FIGURE 23-27 Fuel metabolism in the liver during prolonged fasting or in uncontrolled diabetes mellitus. The numbered steps are described in the text. After depletion of stored carbohydrates (glycogen), gluconeogenesis in the liver becomes the main source of glucose for the brain (blue arrows). ${NH}_{3}$ $NH Subscript 3$ from amino acid deamination is converted into urea and excreted (green arrows). Glucogenic amino acids from protein breakdown (purple arrows) provide substrates for gluconeogenesis, and glucose is exported to the brain. Fatty acids from adipose tissue are imported into the liver and oxidized to acetyl-CoA (orange arrows), and acetyl-CoA is the starting material for ketone body formation in the liver and for export to the brain to serve as an energy source (red arrows). Excess ketone bodies are excreted in the urine.

The liver is shown as a structure with two roughly triangular lobes. Step 1: A fusiform muscle is shown above text that reads, protein degradation yields glucogenic amino acids. A purple arrow points down to a purple box labeled amino acids within the liver. From this box, a green arrow points to N H 3 from which a green arrow points to a green box labeled urea. A green arrow points from urea to a box labeled 2, which reads, Urea is exported to the kidney and excrete d in urine. A green arrow points up to an illustration of a kidney. From the box labeled amino acids, a purple arrow points down to curve up three times to join the citric acid cycle at three different places. The citric acid circle is shown as a dashed curved arrow from oxaloacetate at the nine o’clock position to citrate at the three-o’clock position. A short arrow points from citrate to the four o’clock position, where a purple line from amino acids joins a fifth arrow. A sixth arrow that runs across the six o’clock position is also joined by a purple line from amino acids, Another arrow points from the six-o’clock to seven o’clock positions. An arrow from the seven o’clock position to oxaloacetate is also joined by a purple line from amino acids. A blue arrow points up from oxaloacetate to phosphoenopyruvate. A box labeled 3 reads, Citric acid cycle intermediate (oxaloacetate) is diverted to gluconeogenesis. A blue arrow points from phosphoenopyruvate, from which a blue arrow points up to glucose 6-phosphate. From glucose 6-phosphate, a blue arrow points upward accompanied by a curved arrow showing the low of P subscript i end subscript and then a blue box labeled glucose is produced. A blue arrow points up from glucose to a box labeled 4 that reads, Glucose is exported via the bloodstream to the brain. A blue arrow points from this box to the brain. Adipose tissue is shown to the upper right as a long, roughly triangular mass of spheres. A red arrow points down to a box labeled 5 that reads, Fatty acids (imported from adipose tissue) are oxidized as fuel, producing acetyl Co A. A red arrow points down to an orange box labeled fatty acids in the liver, from which an orange arrow points left to an orange box labeled acetyl-Co A. A dashed black line points down from acetyl-Co A to citrate in the citric acid cycle below and a red arrow points up to acetoacetyl-Co A. A box labeled 6 reads, Lack of oxaloacetate prevents acetyl-Co A entry into the citric acid cycle; acetyl-Co A accumulates. A box labeled 7 reads, Acetyl-Co A accumulation favors ketone body synthesis. An red arrow points up from acetoacetyl-Co A to a red box labeled ketone bodies, from which an arrow points up to a box labeled 8 that reads, Ketone bodies are exported via the bloodstream to the brain, which uses them as fuel. A red arrow points up and branches to point to the brain and to point to a box labeled 9 that reads, Excess ketone bodies end up in urine. A red arrow points from this box to the diagram of a kidney.

Also in the liver, and to some extent in the kidneys, the carbon skeletons of glucogenic amino acids are converted to pyruvate or intermediates of the citric acid cycle. These intermediates (as well as the glycerol derived from TAGs in adipose tissue) provide the starting materials for gluconeogenesis in the liver, yielding glucose for export to the brain. Fatty acids released from adipose tissue are oxidized to acetyl-CoA in the liver, but as oxaloacetate is depleted by the use of citric acid cycle intermediates for gluconeogenesis, entry of acetyl-CoA into the cycle is inhibited and acetyl-CoA accumulates. This favors the formation of acetoacetyl-CoA and ketone bodies. After a few days of fasting, the levels of ketone bodies in the blood rise (Fig. 23-28) as they are exported from the liver to the heart, skeletal muscle, and brain, which use these fuels instead of glucose (Fig. 23-27, ). When the concentration of ketone bodies in the blood exceeds the ability of the kidneys to reabsorb ketones , these compounds begin to appear in the urine.

A graph plots plasma concentration of five chemicals against days of starvation. The chemicals are glucose, free fatty acids, beta-hydroxybutyrate, acetoacetate, and acetone. — FIGURE 23-28 Plasma concentrations of fatty acids, glucose, and ketone bodies during six weeks of starvation. Despite the hormonal mechanisms for maintaining the glucose level in blood, glucose begins to diminish within 2 days of beginning a fast. The levels of ketone bodies, almost unmeasurable before the fast, rise dramatically after 2 to 4 days of fasting, with β-hydroxybutyrate as the major contributor. These water-soluble ketones, acetoacetate and β-hydroxybutyrate, supplement glucose as an energy source for the brain during a long fast. Acetone, a minor ketone body, is not metabolized but is eliminated in the breath. A much smaller rise in blood fatty acids also occurs, but this does not contribute to energy metabolism in the brain, as fatty acids do not cross the blood-brain barrier. [Data from G. F. Cahill, Jr., *Annu. Rev. Nutr.* 26:1, 2006, Fig. 2.]

The horizontal axis is labeled days of starvation and ranges from 0 to 40, labeled in increments of 10. The vertical axis is labeled plasma concentration (m M) and ranges from 0 to 7, labeled in increments of 1. A blue curve labeled glucose begins at (0, 5), drops rapidly to (2, 3.9), then drops slowly to (30, 3.2) before dropping even more slowly to (39, 3). An orange curve labeled free fatty acids begins at (0, 8), rises slightly to (2 1.2), then rises slowly to end at (39, 1.8). A red curve labeled beta-hydroxybutyrate begins at (0, 0), rises rapidly to (12, 4.8), then levels off to end at (39, 5.9). A reed curve labeled acetoacetate begins at (0, 0), rises rapidly to (2, 0.6), then rises gradually to end to (39, 1.5). A red curve labeled acetone begins at (0, 0) and rises almost diagonally to and at (20, 1.7). All data are approximate.

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, in prolonged starvation, to death. Stored fat can provide adequate energy (calories) during a fast or a 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 commonly fortified with vitamins, minerals, and amino acids or proteins.

Epinephrine Signals Impending Activity

When an animal is confronted with a stressful situation that requires increased activity — fighting or fleeing, in the extreme case — neuronal signals from the brain trigger the release of epinephrine and norepinephrine from the adrenal medulla. Both hormones dilate the respiratory passages to facilitate the uptake of $upper O Subscript 2$ $upper O Subscript 2$ , increase the rate and strength of the heartbeat, and raise the blood pressure, thereby promoting the flow of $O_{2}$ $upper O Subscript 2$ and fuels to the tissues (Table 23-6). This is the “fight-or-flight” response.

TABLE 23-6 Physiological and Metabolic Effects of Epinephrine: Preparation for Action

The table consists of 2 columns and 10 rows. Column headings: Immediate effect; Overall effect. Rows 1 through 3 are subcategorized as Physiological. Row 1: Increased heart rate; Increase delivery of O subscript 2 to tissues (muscles). Row 2: Increased blood pressure; Increase delivery of O subscript 2 to tissues (muscles). Row 3: Increased dilation of respiratory passages; Increase delivery of O subscript 2 to tissues (muscles). Rows 4 through 6 are subcategorized as Metabolic. Row 4: Glycogen breakdown (muscle, liver); Increased production of glucose for fuel. Row 5: Decreased glycogen synthesis (muscle, liver); Increase production of glucose for fuel. Row 6: Increased gluconeogenesis (liver); Increase production of glucose for fuel. Row 7: Increased glycolysis (muscle); Increases A T P production of fatty acids as fuels. Row 8: Increased fatty acid mobilization (adipose tissue); Increases availability of fatty acids as fuel. Row 9: Increased glucagon secretion; Reinforce metabolic effects of epinephrine. Row 10: Decreased insulin secretion; Reinforce metabolic effects of epinephrine.

Epinephrine acts primarily on muscle, adipose, and liver tissues. It activates glycogen phosphorylase and inactivates glycogen synthase by cAMP-dependent phosphorylation of the enzymes, thus stimulating the conversion of liver glycogen to blood glucose, the fuel for anaerobic muscular work. Epinephrine also promotes the anaerobic breakdown of muscle glycogen by lactic acid fermentation, stimulating glycolytic ATP formation. The stimulation of glycolysis is accomplished by raising the concentration of fructose 2,6-bisphosphate, a potent allosteric activator of the key glycolytic enzyme phosphofructokinase-1. Epinephrine also stimulates fat mobilization in adipose tissue, by activating hormone-sensitive lipase and moving aside perilipin (see Fig. 17-2). Finally, epinephrine stimulates glucagon secretion and inhibits insulin secretion, reinforcing its effect of mobilizing fuels and inhibiting fuel storage.

Cortisol Signals Stress, Including Low Blood Glucose

A variety of stressors (anxiety, fear, pain, hemorrhage, infection, low blood glucose, starvation) stimulate release of the glucocorticoid cortisol from the adrenal cortex (see Fig. 23-6). Cortisol acts on muscle, liver, and adipose tissue to supply the organism with fuel to withstand the stress. Cortisol is a relatively slow-acting hormone that alters metabolism by changing the kinds and amounts of certain enzymes synthesized in its target cells, rather than by regulating the activity of existing enzyme molecules.

In adipose tissue, cortisol leads to an increased release of fatty acids from stored TAGs. The exported fatty acids serve as fuel for other tissues, and the glycerol is used for gluconeogenesis in the liver. Cortisol stimulates the breakdown of nonessential muscle proteins and the export of amino acids to the liver, where they serve as precursors for gluconeogenesis. In the liver, cortisol promotes gluconeogenesis by stimulating synthesis of PEP carboxykinase; glucagon has the same effect, whereas insulin has the opposite effect. Glucose produced in this way is stored in the liver as glycogen or exported immediately to tissues that need glucose for fuel. The net effect of these metabolic changes is to restore blood glucose to its normal level and to increase glycogen stores, ready to support the fight-or-flight response commonly associated with stress. The effects of cortisol therefore counterbalance those of insulin. During extended periods of stress, the continued release of cortisol loses its positive adaptive value and begins to cause damage to muscle and bone and to impair endocrine and immune function.

Cushing disease is a medical condition in which a tumor on the pituitary gland causes the adrenal glands to overproduce cortisol. It is treated by surgery to remove the tumor, followed by chemotherapy to kill remaining tumor cells. Addison disease results from underproduction of cortisol, and is treated by administering hydrocortisone (the pharmaceutical name for cortisol).

SUMMARY 23.3 Hormonal Regulation of Fuel Metabolism

Fluctuations in blood glucose (normally 70 to 100 mg/100 mL, or about 4.5 mm) due to dietary intake or vigorous exercise are counterbalanced by a variety of hormonally triggered changes in metabolism in several organs.
High blood glucose elicits the release of insulin, which speeds the uptake of glucose by tissues and favors the storage of fuels as glycogen and triacylglycerols while inhibiting fatty acid mobilization in adipose tissue.
Low blood glucose triggers release of glucagon, which stimulates glucose release from liver glycogen and shifts fuel metabolism in liver and muscle to fatty acid oxidation, sparing glucose for use by the brain. In prolonged fasting, TAGs become the principal fuel; the liver converts the fatty acids to ketone bodies for export to other tissues, including the brain.
Epinephrine prepares the body for increased activity by mobilizing glucose from glycogen and other precursors, releasing the glucose into the blood.
Cortisol, released in response to a variety of stressors (including low blood glucose), stimulates gluconeogenesis from amino acids and glycerol in the liver, thus raising blood glucose and counterbalancing the effects of insulin.