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Upon completion of this chapter, the student should be able to answer the following questions:
Explain the different requirements for and utilization by different cells of fuels during the digestive phase as opposed to the interdigestive and fasting phases.
Integrate the structure, synthesis, and secretion of insulin with circulating fuel levels, especially glucose.
Utilize the different signaling pathways regulated by insulin to link insulin to its cellular effects at the molecular level.
Integrate the structure, synthesis, and secretion of glucagon with the levels of circulating fuels, insulin, and catecholamines.
Map out and integrate the actions of insulin on the utilization and storage of glucose, free fatty acids (FFAs), and amino acids (AAs) by hepatocytes, skeletal muscle, and adipocytes during the digestive phase.
Map out and integrate the actions of counterregulatory hormones (glucagon, catecholamines) on the utilization of glucose, the sparing of glucose, and the utilization of FFAs and AAs by hepatocytes, skeletal muscle, and adipocytes during the interdigestive and fasting phases.
Integrate the changes in fuel utilization and hormonal signaling in hepatocytes during the interdigestive and fasting phases that allow for and promote hepatic glucose production and ketogenesis.
Compare signaling pathways that have orexigenic and anorexigenic actions via the hypothalamus.
Link several pathologies related to metabolism, especially those caused by the absolute or relative absence of insulin and by obesity.
There are an estimated 40 trillion cells in the human body, not including the approximately 40 trillion nonhuman cells that comprise the human microbiome. All these cells must continually perform work to stay alive. This work includes maintenance of cellular composition and structural integrity, along with the integrated synthesis and breakdown (i.e., turnover) of macromolecules and organelles. This work also involves the functions of cells that contribute to the human body as a whole (e.g., contraction of the muscle fibers of the diaphragm). Additional work is required of cells when the human body is engaged in a variety of activities, including (but not limited to) manual labor, exercise, and outdoor play; body growth spurt and maturation of the reproductive systems at puberty; pregnancy and breast-feeding; combating an infection or cancer; and the healing of damaged tissues/organs (e.g., healing from surgery). On average, the resting metabolic rate of a relaxed, awake, stationary, healthy adult human accounts for about 70% of their total energy expenditure each day ( Fig. 39.1 ).
To perform this work, cells need fuels, along with the capability to convert fuels into potential chemical energy in the form of adenosine triphosphate (ATP). Cells then convert the energy within ATP into chemical and mechanical work (see Fig. 39.1 ). This means that the need for ATP is immediate and unending, and consequently all living cells must continually synthesize ATP. In fact, humans produce about the equivalent of their body weight in ATP daily. This places a demand on the body to continually supply fuel in some form to all cells. All fuel originates from the diet, but humans do not eat in a nonstop manner all day long. Thus, the constant cellular demand for fuels to make ATP and perform work is paired with an intermittent ingestion of fuels . Diet-derived fuels are oxidized for ATP, but in order to maintain ATP production when not eating for a while (e.g., during sleep), some fuels are stored for future use.
In trying to make sense of energy metabolism, it is important to organize one’s thinking around the following:
Fuels ( Fig. 39.1 ) . Our diet includes both monomeric and polymeric forms (the latter are converted into monomeric forms during digestion and absorption) of the following: (1) monosaccharides, including glucose, fructose, and galactose; (2) long-chain free fatty acids (referred to in this chapter as simply FFAs ); and (3) amino acids (AAs) . The fourth general type of fuel is ketone bodies ( KBs), which are largely absent in the diet. Instead, KBs are produced by hepatocytes via ketogenesis (reaction 14 in Fig. 39.3B ), using FFAs and ketogenic AAs, both of which become abundant during the Fasting Phase. The diet also includes other fuels such as ethanol.
Metabolic Phases. Metabolic Phases refer to the hourly and daily differences in fuel usage and energy metabolism, which are dictated largely by the abundance or scarcity of certain fuels and orchestrated by phase-specific hormones. In general, there are three metabolic phases ( Fig. 39.2 ): (1) the Digestive or Absorptive Phase, which occurs during the 2 to 3 hours it takes to digest a meal; (2) the Interdigestive or Postabsorptive Phase, which normally occurs between meals; and (3) the Fasting Phase, which most commonly occurs between the last snack before bedtime and breakfast. (In fact, physicians refer to a blood value as “fasting,” e.g., “fasting blood glucose,” if the patient abstains from eating after midnight and has blood drawn about 8 AM; prolonged fasting and starvation are more extreme forms of fasting.) Physical exertion, which imposes a heightened energy demand, is another type of metabolic phase that occurs with some frequency and regularity for some individuals. This chapter primarily compares how metabolism differs between the Digestive Phase and the Fasting Phase , and how different hormones orchestrate these metabolic differences.
Metabolic actions of hepatocytes, adipocytes, and skeletal myocytes. All cells are involved in energy metabolism, but these three cell types have a profound impact on whole-body metabolism. During the Digestive Phase, hepatocytes, skeletal myocytes, and adipocytes function largely independently of each other. In contrast, the actions of these three cell types become highly integrated during the Fasting Phase in order to maintain adequate blood glucose levels while providing alternative energy substrates for each cell type. Key features with respect to metabolism of these three cell types are listed in Table 39.1 .
Hepatocytes | Adipocytes | Skeletal Myocytes | |
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Glucose, fed phase |
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Glucose, fasting phase |
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FFA/TG, fed phase |
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FFA/TG, fasting phase |
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AAs, fed phase |
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AAs, fasting phase |
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KBs, fed phase |
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KBs, fasting phase |
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Blood glucose levels . Cells with no or very few mitochondria (e.g., erythrocytes, lens cells of the eye) are absolutely dependent on glucose for energy. Additionally, the central nervous system (CNS) can only use glucose for ATP production under normal conditions. Thus, in the Interdigestive and Fasting Phases, maintenance of blood glucose above a certain minimal threshold is absolutely necessary to avoid CNS-related symptoms, beginning with those caused by a hypoglycemia-activated autonomic response (e.g., nausea, sweating, cardiac arrhythmias). If blood glucose continues to fall, progression to symptoms caused by neuroglycopenia (e.g., cognitive dysfunction, loss of coordinated motor function, and ultimately even coma and death) can occur. This means that whole-body metabolism during the Interdigestive and Fasting Phases must meet the challenge of maintaining blood glucose above 60 mg/dL (see Fig. 39.2 , green arrow ).
Conversely, blood glucose levels must be maintained below an upper threshold (see Fig. 39.2 , red arrow ). This is because glucose is a fairly reactive molecule. High blood glucose leads to high intracellular glucose in many cells, which, in turn, becomes nonenzymatically covalently linked to proteins and other molecules, thereby disrupting their configuration, half-life, and function (see In The Clinic—Glucotoxicity Within Microvasculature).
Insulin and the counterregulatory hormones. Metabolism during the Digestive Phase is orchestrated almost entirely by insulin. During the Fasting Phase, insulin drops to low levels, and this alone allows for some of the metabolic adaptions during the Fasting Phase. In addition, glucagon and catecholamines ( epinephrine, norepinephrine ) stimulate metabolic pathways that integrate the body’s response to an absence of ingested and absorbed fuels. These hormones are referred to as counterregulatory hormones based on their opposition to insulin. Growth hormone (see Chapter 41 ) and cortisol (see Chapter 43 ) also contribute somewhat to Fasting-Phase metabolism.
The basic objectives of the Digestive Phase (see Table 39.1 ) include:
Glucose utilization , in order to prevent prolonged periods of high blood glucose ( Fig. 39.2 ; red arrow ).
Synthesis and storage of fuel polymers (glycogen, triglycerides, proteins) that can be accessed for fuels during the Fasting Phase.
Overall anabolism to maintain the molecular integrity of cells.
The metabolic pathways that fulfill these objectives are driven by insulin , which is the main hormone of the Digestive Phase.
During the Digestive Phase, absorbed fuels are partitioned and used for different purposes. Glucose is the primary fuel used for energy (i.e., ATP production) during the Digestive Phase (refer to Fig. 39.3A for enzymatic pathways). Glucose is considered a universal fuel in that most cells can perform the following:
Import glucose via bidirectional facilitative GLUT transporters (G1, G2, G3, and G4).
“Trap” and “activate” imported glucose by converting glucose into glucose-6-phosphate (G6P) through the activity of one or more hexokinases (Pathway 1). G6P cannot pass through GLUT transporters (“trapping”) and is now a substrate for several enzymatic pathways (“activation”).
Metabolize G6P to pyruvate via the glycolytic pathway, which yields a small amount of ATP without requiring mitochondria or O 2 (Pathway 2). Cells without mitochondria ferment pyruvate to lactate (Pathway 3) and export lactate to the ECF. In contrast, most cells import pyruvate into mitochondria, convert it to acetyl CoA by pyruvate dehydrogenase, and then condense acetyl CoA with oxaloacetate to form citrate. Citrate is cycled through the tricarboxylic acid (TCA) cycle back to oxaloacetate (Pathway 4). This metabolism of pyruvate through the TCA cycle releases CO 2 as waste and generates guanosine triphosphate (GTP) along with flavin adenine dinucleotide hydride (FADH 2 ) and nicotine adenine dinucleotide hydride (NADH). FADH 2 and NADH are used by the electron transport system and oxidative phosphorylation to ultimately generate relatively large amounts of ATP through a process that is absolutely dependent on O 2 (Pathway 5).
The endothelium of the microvasculature of the kidney and retina, as well as the endothelium of the vasa nervosum of the autonomic nervous system, is particularly sensitive to hyperglycemia. Chronically high blood glucose results in pathologically high intracellular levels of glucose in these endothelial cells, resulting in altered protein and lipid structure, oxidative stress, and altered signaling pathways. These insults, collectively referred to as glucotoxicity, cause pathological changes in intracellular and membrane components as well as in secreted molecules that either signal and/or make up the extracellular matrix. Indeed, glucotoxicity is the root cause of the nephropathy, retinopathy, and peripheral neuropathy that occur in poorly controlled diabetes mellitus. Therefore, whole-body metabolism during all metabolic phases must meet the challenge of minimizing the magnitude and duration of the rise in blood glucose associated with ingestion of a meal and must maintain blood glucose below a safe maximal threshold of 100 mg/dL during all other times. Fasting blood glucose between 100 and 124 mg/dL is indicative of impaired glucose tolerance, and values at 125 mg/dL and above are evidence of diabetes mellitus.
Glucose is consumed by erythrocytes and the brain continually throughout all metabolic phases. In contrast, hepatocytes , skeletal myocytes, and adipocytes primarily use glucose during the Digestive Phase. Insulin stimulates glycolysis and entry of pyruvate (end product of glycolysis) into the TCA cycle and oxidative phosphorylation for ATP production in hepatocytes, skeletal myocytes, and adipocytes (see Table 39.1 ).
Hepatocytes express the GLUT2 isoform of the glucose transporter, which is not regulated by insulin for its insertion into the cell membrane. In contrast, skeletal myocytes and adipocytes express the GLUT4 isoform. Newly synthesized GLUT4 exists in an intracellular inactive state with GLUT4 storage vesicles (G4-i in Fig. 39.3B ). Insulin induces translocation and insertion of these GLUT4-rich vesicles into the cell membrane, where GLUT4 can function as an active glucose transporter (G4-m in Fig. 39.3A ).
After its phosphorylation to G6P by glucokinase, hepatocytes convert some of the imported glucose into the storage form, glycogen, during the Digestive Phase ( Fig. 39.3A , Pathway 6). Similarly, skeletal muscle converts some of the G6P from imported glucose into glycogen. Hepatocytes can only store a finite amount of glucose as glycogen. Hepatocytes also convert excess glucose into FFAs through the process of de novo lipogenesis (DNL; Pathway 7 ). These FFAs are typically esterified to glycerol-3-phosphate (G3P) to form triglyceride (TG; Pathway 8), which accumulates as intrahepatic TG during the Digestive Phase. As discussed later for insulin signaling, an excessive accumulation of intrahepatic TG (i.e., fatty liver, hepatic steatosis) can result in insulin resistance.
During the Digestive Phase, AAs are used in multiple anabolic pathways to regenerate degraded molecules, including other AAs, proteins, nucleotides and nucleic acids, glutathione, and complex lipids.
FFAs represent the most efficient fuel type in terms of ATP molecules made per carbon of fuel. However, utilization of FFAs competes effectively with glucose utilization in the mitochondria. High FFA levels during the Digestive Phase would promote a greater magnitude and duration of the glucose surge, thereby contributing to hyperglycemia. Thus, most of the FFAs in an average meal are prevented from entering the circulation by their reesterification into TG and packaging into chylomicrons within the intestinal enterocyte. Chylomicrons are secreted, enter lymphatic vessels and then the blood, and supply adipocytes with FFAs to be stored as TG for use during the Fasting Phase (discussed in more detail later).
The basic objectives of the Fasting Phase include:
Glucose production that maintains blood glucose levels above the lower normal limit ( Fig. 39.2 ; green arrow ). Glucose production is achieved through glycogenolysis and gluconeogenesis in hepatocytes and kidney (see Table 39.1 ).
Glucose sparing , which involves a general decrease in the uptake of glucose by cells, especially by skeletal muscle, and the utilization of FFAs, AAs, and KBs (instead of glucose) for ATP production by most cells. This also helps to maintain adequate blood glucose levels during the Fasting Phase ( Fig. 39.2 ; green arrow ).
Overall catabolism , with the breakdown of polymers into alternate forms of fuel. The metabolic pathways that achieve these objectives are driven by glucagon (liver, adipose tissue), and catecholamines and intracellular metabolic signals (e.g., increased Ca 2+ , increased AMP/ATP ratio). Note also that decreased anabolism reduces cellular ATP needs.
Hepatic glucose production is based on two metabolic pathways (refer to Fig. 39.3B ). The first is the rapid catabolic process of glycogenolysis (Pathway 9). Hepatocytes express the enzyme glucose-6-phosphatase (G6Pase) (Pathway 11), allowing them to convert G6P back to glucose, which can then exit the cell through a bidirectional GLUT2 transporter. Release of glucose derived from glycogenolysis is relatively short lived because the liver glycogen supply becomes exhausted by about 8 hours. The second metabolic contribution to hepatic glucose production during the Fasting Phase is the gradual pathway of gluconeogenesis (Pathway 10). The onset of gluconeogenesis during fasting is slower than glycogenolysis, but gluconeogenesis continues essentially nonstop throughout a Fasting Phase ( Fig. 39.4 ). Gluconeogenesis requires 3-carbon precursors, especially lactate, “gluconeogenic” AAs, and glycerol. How are these precursors supplied during the Fasting Phase? Lactate is continually produced by erythrocytes. Lactate is also produced by glycolytic skeletal muscle fibers during exercise (exercise tends to occur more frequently during the Interdigestive and Fasting Phases as opposed to “on a full stomach”), although much of this lactate is utilized by aerobic skeletal muscle and cardiac muscle during exercise. But additionally, the overall anabolism of the Digestive Phase switches over to a general catabolism during the Fasting Phase (see Fig. 39.3B ). TGs within adipocytes undergo lipolysis to FFAs and glycerol (Pathway 12), and there is a general net proteolysis with the release of AAs during the Fasting state, especially from muscle (Pathway 13). The glycerol and gluconeogenic AAs are released from cells and circulate to the liver, where they are subsequently used for gluconeogenesis (Pathway 10). Thus, gluconeogenesis requires an integration of catabolic pathways in adipocytes and skeletal myocytes with anabolic gluconeogenesis in hepatocytes. Gluconeogenesis eventually supplants glycogenolysis and can continue as long as precursors flow into the liver.
Glucose sparing represents the other general process that contributes to maintenance of adequate blood glucose levels during the Fasting Phase. Glucose sparing means the switching of fuel utilization from glucose to a nongluconeogenic fuel in most cell types, but especially in skeletal muscle, which represents the potentially largest single consumer of glucose. First, the uptake of glucose by skeletal muscle and adipocytes is greatly reduced because the GLUT4 transporter isoform exists in intracellular vesicles and this in an inactive state (G4-i in Fig. 39.3B ) during the Fasting Phase. Thus, alternative fuels need to be delivered to skeletal muscle and adipocytes.
The nongluconeogenic fuels (i.e., cannot be used for gluconeogenesis by the liver) are FFAs and KBs. FFAs are primarily released from adipocytes (Pathway 12) but are also released after packaging of intrahepatic TGs into very low-density lipoproteins (VLDLs) by hepatocytes (discussed later). FFAs are then converted via multiple rounds of β-oxidation (Pathway 16) to acetyl CoAs. KBs are produced via ketogenesis (Pathway 14) in hepatocytes from acetyl CoA, which in turn originates primarily from FFAs and ketogenic AAs, both of which become abundant during the Fasting Phase. KBs are converted back to acetyl CoA via ketolysis (Pathway 15) in nonhepatic cell types. Thus, glucose sparing depends on catabolic adipocyte metabolism, which results in lipolysis of stored TGs and release of FFAs. FFAs are imported by hepatocytes, which use FFAs to produce acetyl CoA. Protein degradation in skeletal muscle and other tissues also makes certain AAs available for ketogenesis. High levels of intramitochondrial acetyl CoA in the hepatocyte not only provides ample carbons for ATP synthesis but serves to: (1) inhibit conversion of pyruvate to acetyl CoA, (2) promote conversion of pyruvate to oxaloacetate for gluconeogenesis, and (3) promote synthesis of KBs (see Fig. 39.3B ). After several days of fasting, the CNS can start using KBs for energy, thereby further sparing glucose for erythrocytes. Many other cell types with mitochondria use KBs along with FFAs for ATP production, especially skeletal muscle. Note however that hepatocytes only carry out ketogenesis, but not ketolysis, as this would form a futile cycle.
The hormones that drive glycogenolysis, gluconeogenesis, lipogenesis, and hepatic ketogenesis as well as VLDL production by the liver during the Fasting Phase are glucagon and catecholamines. In the presence of low glucose, insulin levels fall, and that removes the inhibition by insulin of the secretion of another pancreatic hormone, glucagon. Thus, diminished blood glucose causes a rise in the circulating glucagon-to-insulin ratio. Hepatocytes are the primary target organ of glucagon, which directly drives glycogenolysis (Pathway 9), gluconeogenesis (Pathway 10), ketogenesis (Pathway 14), and FFA oxidation (Pathway 16). Hepatocytes also express β 2 - and α 1 -adrenergic receptors so that norepinephrine from sympathetic innervation and epinephrine from the adrenal medulla (see Chapter 43 ) can reinforce the actions of glucagon. Adipocytes also express the glucagon receptor, as well as the β 2 - and β 3 -adrenergic receptors that respond to catecholamines in response to hypoglycemia, exertion, or certain stresses. Skeletal muscle is not a target of glucagon but does respond to catecholamines stimulation through β 2 -adrenergic receptors. Skeletal muscle is very responsive to intracellular signals, such as Ca ++ , which increases during physical exertion/movement, and to an increase in the adenosine monophosphate (AMP):ATP ratio, which activates AMP kinase.
Finally, it is important to understand that the pathways upregulated during the Fasting Phase are opposed by insulin-dependent pathways that are most active during the Digestive Phase (discussed later). Thus, attenuation of insulin signaling also contributes to the ability of hepatocytes, skeletal myocytes, and adipocytes to display an integrated response to the metabolic challenges of the Fasting Phase.
The islets of Langerhans constitute the endocrine pancreas ( Fig. 39.5A ). Approximately 1 million islets making up about 1% to 2% of the pancreatic mass are spread throughout the exocrine pancreas (see Chapter 27 ). The islets are composed of several cell types, each producing a different hormone. Beta cells make up about three-fourths of the cells of the islets and produce the hormone insulin (see Fig. 39.5B ). Alpha cells account for about 10% of islet cells and secrete glucagon (see Fig. 39.5C ). Other endocrine cell types reside within islets, but their respective hormone products are of marginal or unclear importance and thus will not be discussed further.
Blood flow to the islets is somewhat autonomous from blood flow to the surrounding exocrine pancreatic tissue. Blood flow through the islets passes from beta cells, which predominate in the center of the islet, to alpha and delta cells, which predominate in the periphery (see Fig. 38.5B-C ). Consequently, the first cells affected by circulating insulin are the alpha cells, in which insulin inhibits glucagon secretion.
Insulin is the primary anabolic hormone that dominates regulation of metabolism during the Digestive Phase. Insulin is a protein hormone that belongs to the gene family that includes insulin-like growth factors I and II (IGF-I, IGF-II) and relaxin. Insulin is synthesized as preproinsulin, which is converted to proinsulin as the hormone enters the endoplasmic reticulum. Proinsulin is packaged in the Golgi apparatus into membrane-bound secretory granules. Proinsulin contains the AA sequence of insulin plus the C (connecting) peptide. The proteases that cleave proinsulin (proprotein convertases) are packaged with proinsulin within secretory vesicles. Proteolytic processing clips out the C peptide and generates the mature hormone, which consists of two chains, an α chain and a β chain, connected by two disulfide bridges ( Fig. 39.6 ). A third disulfide bridge is contained within the α chain. Insulin is stored within secretory granules as zinc-bound crystals. Upon stimulation, the granule’s contents are released to the outside of the cell by exocytosis. Equimolar amounts of mature insulin and C peptide are released, along with small amounts of proinsulin. C peptide has no known biological activity but is useful in assessing endogenous insulin production. C peptide is more stable in blood than insulin (making it easier to assay) and helps distinguish endogenous insulin production from injected insulin, insofar as the latter has been purified from C peptide.
Insulin has a short half-life of about 5 minutes and is cleared rapidly from the circulation. It is degraded by insulin-degrading enzyme (IDE; also called insulinase ) in the liver, kidney, and other tissues. Because insulin is secreted into the hepatic portal vein, it is exposed to liver IDE before it enters the peripheral circulation. About half the insulin is degraded before leaving the liver. Thus, peripheral tissues are exposed to significantly less serum insulin concentrations than the liver. Recombinant human insulin and insulin analogs with different characteristics of speed of onset and duration of action and peak activity are now available. Serum insulin levels normally begin to rise within 10 minutes after ingestion of food and reach a peak in 30 to 45 minutes. The higher serum insulin level rapidly lowers blood glucose to baseline values.
Glucose is the primary stimulus of insulin secretion (“steps” in glucose-stimulated insulin secretion (GSIS) described in the discussion that follows refer to Fig. 39.7 ). Entry of glucose into beta cells is facilitated by the GLUT2 transporter (Step 1). Once glucose enters the beta cell, it is phosphorylated to G6P by the low-affinity hexokinase glucokinase (Step 2). Glucokinase is referred to as the “glucose sensor” of the beta cell because the rate of glucose entry is correlated with the rate of glucose phosphorylation, which in turn is directly related to insulin secretion. Metabolism of G6P through glycolysis, the TCA cycle, and oxidative phosphorylation by beta cells increases the intracellular ATP:ADP ratio (Step 3) and closes an ATP-sensitive K + channel (Step 4). This results in depolarization of the beta cell membrane (Step 5), which opens voltage-gated Ca ++ channels (Step 6). Increased intracellular [Ca ++ ] activates microtubule-mediated exocytosis of insulin/proinsulin-containing secretory granules (Step 7).
Ingested glucose has a greater effect on insulin secretion than injected glucose . This phenomenon, called the incretin effect, is due to stimulation by glucose of incretin hormones from the gastrointestinal tract. One clinically relevant incretin hormone is glucagon-like peptide 1 (GLP-1), which is released by L cells of the ileum in response to glucose in the ileal lumen ( Fig. 39.7 ). As a hormone, GLP-1 enters the circulation and ultimately binds to the Gs-coupled GLP1 receptor (GLP1R) on beta cells. This GLP1R/Gs/adenylyl cyclase/protein kinase A (PKA) signaling pathway amplifies the intracellular effects of Ca ++ on insulin secretion. GLP-1 is rapidly degraded in the circulation by dipeptidyl peptidase 4 (DPP-4).
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