Integration of Metabolism PDF

See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/301051919 Integration of Metabolism Chapter · January 2012 DOI: 10.1016/B978-0-323-07155-0.00030-7 CITATION...

See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/301051919 Integration of Metabolism Chapter · January 2012 DOI: 10.1016/B978-0-323-07155-0.00030-7 CITATION READS 1 13,313 2 authors: Gerhard Meisenberg William H. Simmons Ross University, School of Medicine Loyola University Chicago 154 PUBLICATIONS 2,398 CITATIONS 106 PUBLICATIONS 2,270 CITATIONS SEE PROFILE SEE PROFILE Some of the authors of this publication are also working on these related projects: Factor Structure of Wechsler Intelligence Scale for Children -‐Third Edition (WISC – III) among Gifted Students in the Sudan View project Evaluation of Instructors View project All content following this page was uploaded by Gerhard Meisenberg on 12 October 2019. The user has requested enhancement of the downloaded file. These proofs may contain colour figures. Those figures may print black and white in the final printed book if a colour print product has not been planned. The colour figures will appear in colour in all electronic versions of this book. B978-0-323-29616-8.00032-3, 00032 c0160 Chapter 32 INTEGRATION OF METABOLISM p0010 For the individual cell, the most immediate challenge is Glucose the safeguarding of its own energy supply. Beyond the imperative of self-preservation, however, cells and or- gans must cooperate unselfishly for the common good GLUT1,3 of the body. Together they must master the everyday KATP channel Glucose challenges of fasting, feasting, and muscular activity as Glucokinase well as the less routine challenges of infectious illnesses. K+ Glucose-6-phosphate p0015 These challenges require the organism-wide coordi- nation of metabolic pathways, achieved through hor- ADP monal and nervous signals. This chapter discusses the metabolic adaptations to environmental challenges and Membrane ATP varying physiological needs, with special emphasis on hyperpolarization CO + H O 2 2 the challenges posed by overeating and the resulting pathologies. Ca2+ exocytosis s0010 INSULIN IS RELEASED IN RESPONSE TO ELEVATED GLUCOSE Voltage-gated calcium channel p0020 Hormones coordinate the metabolic activities of dif- ferent tissues in response to environmental challenges. Fig. 32.1 Mechanism of glucose-stimulated insulin secretion f0010 Therefore their actions can be understood only in the in pancreatic β-cells. ATP derived from glucose metabolism context of the physiological conditions that cause their closes an ATP-regulated potassium channel (KATP channel), release. thereby depolarizing the membrane and opening voltage-gated p0025 Insulin is the hormone of the well-fed state. It is re- calcium channels. Calcium triggers exocytosis. , stimulation; , inhibition. leased by the β-cells in the islets of Langerhans when the levels of blood glucose and other nutrients rise after a Comp. by: Sathish Stage: Revises2 Chapter No.: 32 Title Name: Meisenberg meal. There are approximately 1 million islets in the hu- In consequence, the β-cells metabolize glucose at an p0035 man pancreas. β-Cells make up 50% of their cell popula- increased rate when the blood glucose level is high, and tion, and another 35% to 40% are glucagon-­producing this raises the ATP/ADP ratio in the cell. The plasma α-cells. The remainder are somatostatin-producing membrane of the β-cells contains an ATP-regulated po- δ-cells and pancreatic polypeptide–producing PP-cells. tassium channel (KATP channel) that is leaky when the p0030 Glucose is both the main energy source for the β-cells intracellular ATP concentration is low but closes more Page Number: 533 Date: 24/08/2016 Time: 09:10:58 and the most important stimulus for insulin secretion. tightly when the ATP level is high. In consequence, The two functions are coupled in the major pathway of rising ATP caused by increased glucose supply closes glucose-induced insulin secretion that is summarized in the channel and thereby partly depolarizes the plasma Fig. 32.1. Insulin enters the cell on GLUT1 and GLUT3 membrane. Weakening of the membrane potential opens carriers. While GLUT3 is a high-affinity carrier (Km for voltage-gated calcium channels. The calcium entering glucose 1 mM), GLUT1 has a Km of 6 mM, a bit above through these channels triggers the exocytosis of insulin- the fasting blood glucose level. In the cell, glucose is containing vesicles and induces longer-term adaptations phosphorylated by glucokinase. With a Km for glucose leading to increased insulin synthesis. of about 6 mM and a mildly sigmoidal relationship To a lesser extent, insulin secretion is stimulated by p0040 between glucose concentration and reaction rate, glu- nutrients other than glucose, including amino acids, cokinase can function as a glucose sensor (along with fatty acids, and ketone bodies. It is also stimulated by GLUT1). acetylcholine from the vagus nerve and by incretins, 533 Meisenberg, 978-0-323-29616-8 To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s), editor(s), reviewer(s), Elsevier and typesetter SPi. It is not allowed to publish this proof online or in print. This proof copy is the copyright property of the publisher and is confidential until formal publication. These proofs may contain colour figures. Those figures may print black and white in the final printed book if a colour print product has not been planned. The colour figures will appear in colour in all electronic versions of this book. B978-0-323-29616-8.00032-3, 00032 534 METABOLISM i­nsulin-releasing hormones from the gastrointestinal g­ lucose-metabolizing enzymes are stimulated by i­nsulin. tract. While acetylcholine releases calcium from the en- Insulin induces the synthesis of glycolytic enzymes doplasmic reticulum, the incretins enhance insulin secre- and represses the synthesis of gluconeogenic enzymes tion through cyclic AMP. on a time scale of hours to days. The effects on gluco­ neogenesis are mediated mainly by inhibition of the FoxO transcription factor. On a minute-by-minute time s0015 INSULIN STIMULATES THE UTILIZATION scale, insulin stimulates glycogen synthesis and glycoly- OF NUTRIENTS sis while inhibiting glycogenolysis and gluconeogenesis p0045 The list of insulin effects given in Table 32.1 shows that by reversing cAMP-induced phosphorylations. This is insulin channels excess nutrients into the synthesis of achieved by two mechanisms: glycogen, fat, and protein. p0050 After a carbohydrate-rich meal, more than half of the 1. Insulin stimulates phosphodiesterase 3B, which de- o0010 excess glucose is metabolized in skeletal muscle, 20% to grades cAMP to AMP. 25% in the liver, and 10% in adipose tissue. The mech- 2. Insulin stimulates phosphatase-1, the enzyme that o0015 anisms by which insulin stimulates glucose metabolism dephosphorylates the important targets of the cAMP- are different in different tissues. In skeletal muscle and ­activated protein kinase A: glycogen synthase, ­glycogen adipose tissue, insulin stimulates glucose uptake by the phosphorylase, phosphorylase kinase, ­ PFK-2, and glucose carrier GLUT4. In the absence of insulin, most ­others (see Chapter 24). GLUT4 transporters are located in the membrane of in- tracellular storage vesicles. Only 5% are on the cell sur- Glucose metabolism in brain and erythrocytes is not in- face. Insulin causes the storage vesicles to move to the sulin dependent. These tissues are inept at metabolizing cell surface and fuse with the plasma membrane, thereby alternative fuels. They must keep consuming glucose, depositing GLUT4 in the plasma membrane. The pro- even in the fasting state, when the insulin level is low. cess is mediated through the insulin receptor substrate, Insulin’s most important effect on fat metabolism p0075 ­phosphoinositide 3-kinase, and protein kinase B (Akt) is a powerful inhibition of lipolysis in adipose tissue. but not through the Ras–MAP kinase pathway or mTOR. This ensures that dietary nutrients rather than fatty p0055 In the liver, glucose uptake by the insulin-­insensitive acids from adipose tissue are metabolized in the well- GLUT2 transporter is not rate limiting, but the fed state. In the liver it induces the conversion of excess t0010 Table 32.1 Metabolic Effects of Insulin Tissue Affected Pathway Affected Enzyme Liver ↑ Glucose phosphorylation Glucokinase ↑ Glycolysis Phosphofructokinase-1,* pyruvate kinase† ↓ Gluconeogenesis PEP-carboxykinase, fructose-1,6-bisphosphatase,* glucose-6-phosphatase ↑ Glycogen synthesis Glycogen synthase† ↓ Glycogenolysis Glycogen phosphorylase† ↑ Fatty acid synthesis Acetyl-CoA carboxylase,† ATP-citrate lyase, malic enzyme ↑ Pentose phosphate pathway Glucose-6-phosphate dehydrogenase Adipose tissue ↑ Glucose uptake Glucose carrier ↑ Glycolysis Phosphofructokinase-1 ↑ Pentose phosphate pathway Glucose-6-phosphate dehydrogenase ↑ Pyruvate oxidation Pyruvate dehydrogenase† ↑ Triglyceride utilization (from lipoproteins) Lipoprotein lipase ↑ Triglyceride synthesis Glycerol-3-phosphate acyl transferase ↓ Lipolysis Hormone-sensitive lipase† Skeletal muscle ↑ Glucose uptake Glucose carrier ↑ Glycolysis Phosphofructokinase-1 ↑ Glycogen synthesis Glycogen synthase† ↓ Glycogenolysis Glycogen phosphorylase† ↑ Protein synthesis Translational initiation complex Most of the other insulin effects included here are actions on the rate of synthesis or degradation of the affected enzyme. PEP, Phosphoenolpyruvate. * Insulin acts indirectly by promoting the dephosphorylation of phosphofructokinase-2/fructose-2,6-bisphosphatase, thereby increasing the level of fructose-2,6-bisphosphate. † Insulin acts by promoting the dephosphorylation of the enzyme. Meisenberg, 978-0-323-29616-8 To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s), editor(s), reviewer(s), Elsevier and typesetter SPi. It is not allowed to publish this proof online or in print. This proof copy is the copyright property of the publisher and is confidential until formal publication. These proofs may contain colour figures. Those figures may print black and white in the final printed book if a colour print product has not been planned. The colour figures will appear in colour in all electronic versions of this book. B978-0-323-29616-8.00032-3, 00032 Integration of Metabolism 535 c­ arbohydrate to fat through glycolysis, pyruvate dehy- Leucine and arginine are especially effective, although drogenase reaction, and fatty acid biosynthesis. their mechanism of action is not fully known. However, once at the lysosomal membrane, mTOR can be acti- vated by other stimuli. Most of them act through the s0020 PROTEIN SYNTHESIS IS COORDINATED BY THE tuberous sclerosis complex (TSC complex in Fig. 32.2), mTOR COMPLEX which is coupled to mTORC1 though the G protein p0080 Insulin stimulates protein synthesis as well as carbohy- Rheb. The active, GTP-bound form of Rheb activates drate utilization. It can act as a growth factor by stim- mTORC1, and the TSC complex inactivates Rheb by ulating cell growth or proliferation (depending on the stimulating its GTPase activity. Hence, the TSC complex cell type) through the Ras protein and the MAP kinase inhibits mTORC1. cascade, leading to the activation of the extracellular The stimuli that regulate the TSC complex include p0100 signal–regulated kinases ERK1 and ERK2. the usual suspects. Insulin and growth factors, acting p0085 Insulin actions on protein synthesis are mediated by through tyrosine protein kinase receptors, inhibit the the mTOR (mammalian target of rapamycin, or mecha- TSC complex (thereby activating mTORC1) by in- nistic target of rapamycin) complex. The core component hibitory phosphorylations, both through Akt and the of this complex is a protein kinase that phosphorylates extracellular signal–regulated kinases (ERKs). Other numerous target proteins on serine and threonine side signaling cascades that impinge on the TSC complex chains. It forms two complexes that share some of their include the Wnt cascade, which we encountered as a subunits but not others: mTOR complex 1 (mTORC1) ­cancer-promoting signaling system in Chapter 19. assembles on the surface of the lysosome membrane, Nutrient deficiency inhibits mTORC1 by activating p0105 and mTOR complex 2 (mTORC2) assembles under the the AMP-activated protein kinase, which activates the plasma membrane. TSC complex. Also other cellular stresses, including p0090 Both mTOR complexes mediate cellular adaptations DNA damage, endoplasmic reticulum stress, and hy- to nutrient availability. Little is known about the precise poxia, can activate the TSC complex through various roles of mTORC2, except that it is involved in the early mechanisms. steps of insulin signaling leading to the activation of The effects of mTORC1 activation are shown in p0110 Akt2, the insulin-regulated isoenzyme of protein kinase Fig. 32.3. Most prominent are effects on global protein B. Far more is known about the functions of mTORC1. metabolism. Ribosomal protein synthesis is increased This complex integrates signals of nutrient availabil- rather nonspecifically by two mechanisms. One is phos- ity and coordinates the appropriate cellular responses. phorylation of 4EBP (4E binding protein), an inhibitor Fig. 32.2 shows the main mechanisms by which its ac- of eukaryotic initiation factor 4E. The phosphorylation tivity is regulated. inactivates this inhibitor. A second mechanism is an ac- p0095 Attachment of mTORC1 to the lysosomal membrane tivating phosphorylation of S6 kinase, which facilitates depends on the small G proteins Rag A/B and Rag C/D. protein synthesis by phosphorylating, among other sub- These G proteins are activated by free amino acids. strates, one of the ribosomal proteins. Insulin Growth factors Comp. by: Sathish Stage: Revises2 Chapter No.: 32 Title Name: Meisenberg R GTP– Ras PI3K Low Wnt ERK Akt energy Page Number: 535 Date: 24/08/2016 Time: 09:10:58 AMPK TSC GSK3 R p53 Amino GTP– Rheb mTORC1 acids Fig. 32.2 Activation of mTOR complex 1 f0015 (mTORC1) on the surface of the lysosomal DNA damage Rag –GTP membrane. Akt, Akt protein kinase (protein kinase B); AMPK, AMP-activated protein kinase; ERK, extracellular signal regulated kinases; Lysosome GSK3, glycogen synthase kinase-3; mTORC1, mTOR complex 1; PI3K, phosphoinositide 3-kinase; R, receptors; Rag, Ras, Rheb, GTP- binding signaling proteins; TSC, tuberous sclerosis complex. , stimulation; , inhibition. Meisenberg, 978-0-323-29616-8 To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s), editor(s), reviewer(s), Elsevier and typesetter SPi. It is not allowed to publish this proof online or in print. This proof copy is the copyright property of the publisher and is confidential until formal publication. These proofs may contain colour figures. Those figures may print black and white in the final printed book if a colour print product has not been planned. The colour figures will appear in colour in all electronic versions of this book. B978-0-323-29616-8.00032-3, 00032 536 METABOLISM Nutrients Growth factors Energy Insulin f0020 Fig. 32.3 Effects of active mTOR complex 1 (mTORC1) on cell metabolism. 4EBP, Binding mTORC 1 Lipid SREBP-1c protein for translational initiation factor 4E; HIF1α synthesis HIF1α, hypoxia-inducible factor 1α; c-Myc, 4EBP c-Myc Glycolysis cellular Myc protein; S6 kinase, ribosomal S6 kinase ZKSCAN3 subunit protein 6 kinase; SREBP-1c, sterol TFEB response element binding protein-1c; TFEB, transcription factor EB; ZKSCAN3, zinc finger Protein synthesis Autophagy protein harboring KRAB and SCAN domains-3 Lysosomal (a transcription factor). , stimulation; biogenesis , inhibition. p0115 The stimulation of protein synthesis is complemented c­ annot oxidize fatty acids and therefore depend on a steady by the inhibition of lysosomal biogenesis and a­ utophagy. supply of glucose. Glucagon is specialized for the mainte- These effects are mediated by the phosphorylation of nance of a normal blood glucose level during fasting. Its transcription factors, whose translocation from the cy- secretion from the pancreatic α-cells increases twofold to toplasm to the nucleus is regulated by mTOR-induced threefold in response to hypoglycemia and is reduced to phosphorylations. Thus mTOR’s anabolic effects in- half of the basal release by hyperglycemia. Acting through clude increased protein synthesis and reduced lysosomal its second messenger cyclic AMP (cAMP), glucagon stim- protein degradation. ulates hepatic glucose production by glycogenolysis and p0120 In addition to protein turnover, mTOR affects the gluconeogenesis. Its actions on the pathways of glucose major pathways of carbohydrate and lipid metabo- metabolism are opposite those of insulin (Table 32.2), lism. It increases fatty acid biosynthesis by stimulating but unlike insulin, glucagon acts almost exclusively on the the cleavage of SREBP-1c, one of the master regulators liver; its effects on adipose tissue, muscle, and other extra- of lipid metabolism (see Chapter 25). Stimulation of hepatic tissues are negligible in humans. glycolysis can be achieved through hypoxia inducible factor-1α and the Myc protein, a transcription factor CATECHOLAMINES MEDIATE THE FLIGHT-OR- s0030 encoded by the cellular MYC proto-oncogene. FIGHT RESPONSE Next to fasting, physical exertion is a recurrent chal- p0130 s0025 GLUCAGON MAINTAINS THE BLOOD GLUCOSE lenge for human metabolism. Energy generation in the LEVEL muscles needs to be augmented enormously, and energy p0125 During starvation, the body covers most of its energy needs has to be supplied to the muscles from stored liver gly- from adipose tissue–derived fatty acids. However, neu- cogen and adipose tissue triglycerides. These responses rons and other specialized cell types, such as ­erythrocytes, are coordinated by the catecholamines norepinephrine t0015 Table 32.2 Metabolic Effects of Glucagon on the Liver* Enzyme Affected by Enzyme Enzyme Effect on Pathway Affected Enzyme Induction/Repression Phosphorylation Other ↓ Glycolysis Glucokinase + Phosphofructokinase-1 +† Pyruvate kinase + ↑ Gluconeogenesis PEP-carboxykinase + Fructose-1,6-bisphosphatase + +† Glucose-6-phosphatase + ↓ Glycogen synthesis Glycogen synthase + ↑ Glycogenolysis Glycogen phosphorylase + ↓ Fatty acid synthesis Acetyl-CoA carboxylase + + ↑ Fatty acid oxidation Carnitine-palmitoyl transferase-1 + CoA, Coenzyme A; PEP, phosphoenolpyruvate. *Both the enzyme phosphorylations and the effects on gene expression are mediated by cyclic AMP (cAMP). † Mediated by the cAMP-dependent phosphorylation of phosphofructokinase-2/fructose-2,6-bisphosphatase and a decreased cellular concentration of fructose-2,6-bisphosphate. Meisenberg, 978-0-323-29616-8 To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s), editor(s), reviewer(s), Elsevier and typesetter SPi. It is not allowed to publish this proof online or in print. This proof copy is the copyright property of the publisher and is confidential until formal publication. These proofs may contain colour figures. Those figures may print black and white in the final printed book if a colour print product has not been planned. The colour figures will appear in colour in all electronic versions of this book. B978-0-323-29616-8.00032-3, 00032 Integration of Metabolism 537 t0020 Table 32.3 Metabolic Effects of Norepinephrine and Epinephrine Tissue Affected Pathway Affected Enzyme Second Messenger Adipose tissue ↑↑↑ Lipolysis Hormone-sensitive lipase* cAMP ↓ Triglyceride utilization from lipoproteins Lipoprotein lipase‡ Liver ↓ Glycolysis Phosphofructokinase-1† cAMP ↑ Gluconeogenesis Fructose-1,6-bisphosphatase† ↓↓ Glycogen synthesis Glycogen synthase* Ca2+, cAMP ↑↑↑ Glycogenolysis Glycogen phosphorylase* ↓ Fatty acid synthesis Acetyl-CoA carboxylase* cAMP Skeletal muscle ↑↑↑ Glycolysis Phosphofructokinase-1† ↓↓ Glycogen synthesis Glycogen synthase* cAMP ↑↑↑ Glycogenolysis Glycogen phosphorylase* ↑ Triglyceride utilization from lipoproteins Lipoprotein lipase ? ↑ and ↓, Weak or inconsistent effect; ↑↑ and ↓↓, moderately strong effect; ↑↑↑ and ↓↓↓, strong effect. cAMP, Cyclic adenosine monophosphate. *Effects mediated by enzyme phosphorylation. † Mediated indirectly by phosphorylation of phosphofructokinase-2/fructose-2,6-bisphosphatase. ‡ Decreased translation. (noradrenaline) and epinephrine (adrenaline). The cat- g­ luconeogenesis and glycogen synthesis in an attempt to echolamines are stress hormones. They are released not build up liver glycogen stores for the activities of the day. only during physical exertion, but also in response to Cortisol is also a stress hormone. Especially chronic p0155 psychological stress. In ancestral environments, stress stress stimulates cortisol secretion from the adrenal usually meant the need to be prepared for physical ef- cortex through corticotropin-releasing hormone from fort: the flight-or-fight response. the hypothalamus and adrenocorticotropic hormone p0135 The catecholamines can raise the cellular cAMP level (ACTH) from the anterior pituitary gland. through β-adrenergic receptors and the calcium level By and large, the actions of the glucocorticoids p0160 through α1-adrenergic receptors. Muscle and adipose (Table 32.4) are synergistic with epinephrine, but there tissue have mainly β receptors, and the liver has both β is an important difference. Epinephrine works through and α1 receptors. the second messengers cAMP and calcium, whereas the p0140 Table 32.3 summarizes the important metabolic ef- glucocorticoids are mainly gene regulators. Therefore fects. Some are tissue specific. For example, glycolysis is epinephrine induces its effects in a matter of seconds, inhibited in the liver but stimulated in muscle. The reg- but most glucocorticoid effects are cumulative over ulatory metabolite fructose-2,6-bisphosphate activates hours to days. phosphofructokinase-1 in muscle, as it does in the liver The glucocorticoids prepare the body for the action p0165 (see Chapter 24). However, the phosphofructokinase- of epinephrine. They stimulate the synthesis of the adi- 2/fructose-2,6-bisphosphatase of skeletal muscle is dif- pose tissue lipases. They also increase gluconeogenesis ferent from the liver enzyme. Its kinase activity is not from amino acids by causing net protein breakdown inhibited but is stimulated by cAMP-induced phosphor- in peripheral tissues and inducing phosphoenolpyru- Comp. by: Sathish Stage: Revises2 Chapter No.: 32 Title Name: Meisenberg ylation. Therefore the catecholamines, acting through β vate (PEP) carboxykinase in the liver. Excess glucose-6-­ receptors and cAMP, stimulate rather than inhibit gly- phosphate produced by gluconeogenesis is diverted into colysis in skeletal muscle. glycogen synthesis, thus providing more substrate for p0145 The catecholamines are functional antagonists of epinephrine-induced glycogenolysis. insulin that raise the blood levels of glucose and fatty acids. They are not very important for blood glucose Page Number: 537 Date: 24/08/2016 Time: 09:10:58 regulation under ordinary conditions, but their release Table 32.4 Important Metabolic Actions of Cortisol and Other t0025 is potently stimulated by hypoglycemia. Therefore hy- Glucocorticoids* poglycemic episodes in metabolic diseases are always Tissue Affected Pathway Affected Enzyme accompanied by signs of excessive sympathetic activity Adipose tissue ↑ Lipolysis Lipases including pallor, sweating, and tachycardia. Muscle tissue ↑ Protein degradation ? Liver ↑ Gluconeogenesis Enzymes of amino acid s0035 GLUCOCORTICOIDS ARE RELEASED IN CHRONIC catabolism, PEP-carboxykinase STRESS ↑ Glycogen synthesis Glycogen synthase p0150 Glucocorticoids have two physiological functions. One PEP, Phosphoenolpyruvate. is the circadian control of metabolic pathways. Cortisol * The glucocorticoid effects are mediated by altered rates of enzyme is highest in the early morning, when it stimulates synthesis. Meisenberg, 978-0-323-29616-8 To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s), editor(s), reviewer(s), Elsevier and typesetter SPi. It is not allowed to publish this proof online or in print. This proof copy is the copyright property of the publisher and is confidential until formal publication. These proofs may contain colour figures. Those figures may print black and white in the final printed book if a colour print product has not been planned. The colour figures will appear in colour in all electronic versions of this book. B978-0-323-29616-8.00032-3, 00032 538 METABOLISM p0170 It now is apparent how cortisol and epinephrine with predictive formulas, for example, the Harris- cooperate in a stressful situation. During an extended Benedict equation: hunting expedition by a stone-age caveman, cortisol in- duced the lipases in his adipose tissue and built up the glycogen stores in his liver. As soon as the hunter was attacked by a cave bear, epinephrine immediately stim- ulated the release of fatty acids from adipose tissue and of glucose from the liver. Thanks to the supply of these fuels to his muscles, the caveman managed to dodge the cave bear’s attack and kill the animal with his club. This gave him the chance to transmit his metabolic regulator or the Mifflin-St. Jeor equation: genes to us, his descendants. p0175 For the caveman’s degenerate descendants today, the BMR = Constant + ( 9.99 ´ Weight ) + stress hormones are troublemakers rather than lifesav- ( 6.25 ´ Height ) - ( 4.92 ´ Age ) ers. Patients suffering from infections, autoimmune dis- eases, malignancies, injuries, surgery, or psychological where Constant = 5 for males and −161 for females. upheaval have elevated levels of glucocorticoids and In these equations, BMR is calculated as kilocalories p0200 catecholamines. Cortisol-induced protein breakdown per day. Weight is measured in kilograms, height in cen- leads to negative nitrogen balance and muscle wasting. timeters, and age in years. Because the stress hormones oppose the metabolic effects BMR depends on body composition. Men tend to have a p0205 of insulin, seriously ill patients have insulin resistance higher BMR per body weight than do women because men and poor glucose tolerance. The insulin requirement of have relatively more muscle than fat (Table 32.5). Women insulin-dependent diabetic patients rises substantially need more fat as an energy reserve for pregnancy, and men during otherwise harmless infections or other illnesses. need more muscle to fight over the women. It also depends p0180 Some cytokines, which are released by white blood on dietary history. In extended starvation, the BMR declines cells during infections and other diseases, have meta- because less thyroxine is converted to T3 in the tissues. bolic effects similar to the stress hormones. Interleukin-1 On top of the BMR, additional energy is spent for p0210 stimulates proteolysis in skeletal muscle, and tumor ne- postprandial thermogenesis after a meal. It is produced crosis factor promotes lipolysis in adipose tissue. These by metabolic interconversions and increased biosynthesis mediators contribute to the weight loss that is common after a meal, and by increased futile cycling in metabolic in patients with malignancies or chronic infections. pathways. Postprandial thermogenesis depends on the size and composition of the meal. The digestion, absorp- tion, and storage of fat require only 2% to 4% of the fat s0040 ENERGY IS EXPENDED CONTINUOUSLY energy, but the conversion of carbohydrate to storage fat p0185 The basal metabolic rate (BMR) is the amount of energy requires 24% of the energy content of the carbohydrate. that a resting person consumes in the “postabsorptive” Muscular activity is the most variable item in the p0215 state, 8 to 12 hours after the last meal. It is calculated energy budget but is generally less than 1500 kcal/day t0030 Table 32.5 Metabolic Rates of Various Organs and Tissues Tissue or Organ Percent of Metabolic Rate Organ Weight (kg) Body Weight (% of Total) Metabolic Rate (kcal/ Child Child Child kg/day) Male Female (6 Months) Male Female (6 Months) Male Female (6 Months) Liver 200 1.8 1.4 0.26 2.57 2.41 3.51 21 21 14 Brain 240 1.4 1.2 0.71 2.00 2.07 9.51 20 21 44 Heart 440 0.33 0.24 0.04 0.47 0.41 0.53 9 8 4 Kidneys 440 0.31 0.28 0.05 0.44 0.47 0.71 8 9 6 Muscle 13 28 17 1.88 40 29.3 25 22 16 6 Adipose 4.5 15 19 1.50 21.4 32.8 20 4 6 2 tissue Others 12 23.2 18.9 3.06 33.1 32.6 40.7 16 19 24 Total 70 58 7.50 100 100 100 100* 100† 100‡ Data from Kinney JM, Tucker HN: Energy metabolism, New York, 1992, Raven Press. † ‡ *1680 kcal/day. 1340 kcal/day. 390 kcal/day. Meisenberg, 978-0-323-29616-8 To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s), editor(s), reviewer(s), Elsevier and typesetter SPi. It is not allowed to publish this proof online or in print. This proof copy is the copyright property of the publisher and is confidential until formal publication. These proofs may contain colour figures. Those figures may print black and white in the final printed book if a colour print product has not been planned. The colour figures will appear in colour in all electronic versions of this book. B978-0-323-29616-8.00032-3, 00032 Integration of Metabolism 539 except in people who engage in very strenuous physical death on a hunger strike depends on the fat reserves, but labor all day long. survival times around 100 days are typical. p0220 Multipliers are used to calculate the caloric expendi- Compared with fat reserves, glycogen stores are p0235 ture (and dietary requirement) for different physiologi- puny. Liver glycogen is depleted within a day. Glycogen cal states: is a checking account from which withdrawals are Long  term fasting : BMR ´ 0.8 made on an hour-by-hour basis, whereas fat is a sav- ings account. Sedentary lifestyle : BMR ´ 1.2 Unlike fat and glycogen, protein is not a specialized p0240 Lightly active : BMR ´ 1.375 energy storage form. Still, much of the protein in muscle Moderately active : BMR ´ 1.55 and other tissues can be mobilized during fasting. Only Very active : BMR ´ 1.725 the protein in brain, liver, kidneys, and other vital or- gans is taboo, even during prolonged starvation. Extremely active : BMR ´ 1.9 During long-term fasting, net protein breakdown p0245 is required to supply amino acids for gluconeogenesis. s0045 STORED FAT AND GLYCOGEN ARE DEGRADED Because even-chain fatty acids are not substrates of glu- BETWEEN MEALS coneogenesis, only amino acids are available in suffi- p0225 Energy is spent round the clock, but most people eat in cient quantity to cover the glucose requirement during well-spaced meals. An ample supply is available for only fasting. Therefore the loss of protein from muscle and 3 to 4 hours after a meal. For the rest of the day, we other tissues is inevitable during prolonged fasting. depend on stored energy reserves. Fig. 32.4 shows some of the changes in blood chem- p0250 p0230 Compared with free-living animals, humans have an istry during the transition from the well-fed state to enormous amount of fat (Table 32.6), which keeps us starvation. The most important hormonal factor is the alive during extended fasting. It is easy to calculate that balance between insulin and its antagonists, especially with fat stores of 16 kg (a typical amount for the non- glucagon. During fasting, the plasma level of insulin obese) and BMR of 1500 kcal/day, people can survive falls, whereas first epinephrine, then glucagon, and fi- for about 100 days on tap water and vitamin pills alone, nally cortisol levels rise. actually 125 days if we assume that the metabolic rate During the first few days on a zero-calorie diet, p0255 in prolonged fasting is 20% below BMR. The time to between 70 and 150 g of body protein is lost per t0035 Table 32.6 Energy Reserves of the “Textbook” 70-kg Man Stored Nutrient Tissue Amount Stored (kg) Energy Value (kcal) Triglyceride Adipose tissue 10–15 90,000–140,000 Glycogen Muscle 0.3 1200 Liver 0.08* 320* Protein Muscle 6–8 30,000–40,000 * After a meal. Liver glycogen is approximately 20% to 30% of this value after an overnight fast of 12 hours. Comp. by: Sathish Stage: Revises2 Chapter No.: 32 Title Name: Meisenberg Glucose pg/mL µU/mL Glucagon pg/mL glucagon insulin Insulin µU/mL 5 “Free” fatty acids Ketone bodies Nutrient level (mM) 150 Hormone level 4 40 Page Number: 539 Date: 24/08/2016 Time: 09:10:58 3 30 100 2 20 50 1 10 4 8 12 16 20 24 2 3 4 5 6 3 Weeks Hours Days f0025 Fig. 32.4 Plasma levels of hormones and nutrients at different times after the last meal. mM, mmol/liter. Meisenberg, 978-0-323-29616-8 To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s), editor(s), reviewer(s), Elsevier and typesetter SPi. It is not allowed to publish this proof online or in print. This proof copy is the copyright property of the publisher and is confidential until formal publication. These proofs may contain colour figures. Those figures may print black and white in the final printed book if a colour print product has not been planned. The colour figures will appear in colour in all electronic versions of this book. B978-0-323-29616-8.00032-3, 00032 540 METABOLISM day. The rate of protein loss then declines in parallel acids rise fourfold to eightfold, and ketone ­b odies with the ­rising use of ketone bodies. Nevertheless, 1 kg (β-hydroxybutyrate and acetoacetate) rise up to of protein is lost within the first 15 days of starvation. 100-fold. p0260 Adding 100 g of glucose to the zero-calorie diet re- Plasma free fatty acids are low after a carbohydrate p0270 duces the need for gluconeogenesis and cuts the protein meal because insulin inhibits lipolysis in adipose tis- loss by 40%. The addition of 55 g of protein per day to sue. They are moderately high after a fat meal, because the zero-calorie diet cannot prevent a negative nitrogen some of the fatty acids released by lipoprotein lipase balance initially, but many subjects regain nitrogen equi- bind to albumin, which carries them to distant parts of librium after about 20 days. the body. Insulin stimulates lipoprotein lipase in adi- pose tissue but not in muscle after a meal, thus routing the dietary triglycerides in chylomicrons to adipose s0050 ADIPOSE TISSUE IS THE MOST IMPORTANT tissue (Fig. 32.5). ENERGY DEPOT During fasting, fat synthesis in adipose tissue is re- p0275 p0265 The blood glucose level declines only to a limited duced while lipolysis is stimulated by the combina- extent even during prolonged fasting, but free fatty tion of the low insulin level and high levels of insulin (VLDL) Chylomicrons Remnants To liver Fatty acids Glucose + LPL + Glycerol Glucose Fatty acids + + – Acyl-CoA Acetyl-CoA + Triglycerides Glycerol- P TCA cycle A To muscle and other tissues To liver (for oxidation) (for gluconeogenesis) To liver VLDL (for ketogenesis) Glucose IDL Glycerol Fatty acids LPL Glycerol Fatty acids Glucose Acyl-CoA Acetyl-CoA Triglycerides Glycerol- P TCA cycle B f0030 Fig. 32.5 Metabolism of adipose tissue after a mixed meal containing all major nutrients and during fasting. A, After a meal. Insulin-stimulated or insulin-inhibited steps are marked by + or −, respectively. B, During fasting. CoA, Coenzyme A, IDL, intermediate-density lipoprotein (VLDL remnant); LPL, lipoprotein lipase; TCA, tricarboxylic acid, VLDL, very-low-density lipoprotein. Meisenberg, 978-0-323-29616-8 To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s), editor(s), reviewer(s), Elsevier and typesetter SPi. It is not allowed to publish this proof online or in print. This proof copy is the copyright property of the publisher and is confidential until formal publication. These proofs may contain colour figures. Those figures may print black and white in the final printed book if a colour print product has not been planned. The colour figures will appear in colour in all electronic versions of this book. B978-0-323-29616-8.00032-3, 00032 Integration of Metabolism 541 a­ ntagonists. Non-diabetic adipose tissue is very sensitive of the rest is metabolized by glycolysis, but amino to insulin, and lipolysis is inhibited even at moderately acids rather than glucose provide most of the liv- high insulin levels during the early stages of fasting. er’s energy needs after a mixed meal. Much of the acetyl-­ coenzyme A (acetyl-CoA) from glycolysis is channeled into the synthesis of fatty acids and tri- s0055 THE LIVER CONVERTS DIETARY CARBOHYDRATES glycerides. In the liver, glycolysis is the first step in TO GLYCOGEN AND FAT AFTER A MEAL the conversion of carbohydrate to fat. Triglycerides p0280 Being devoid of lipoprotein lipase, the liver is not and other lipids from endogenous synthesis in the a major consumer of triglycerides after a meal al- liver are exported as constituents of very-low-density though it obtains some triglyceride from chylo- lipoprotein (VLDL). Insulin ­coordinates this process micron remnants. However, the liver metabolizes by stimulating both glycolysis and fatty acid biosyn- between 20% and 25% of the dietary glucose after a thesis (Fig. 32.6). ­carbohydrate-rich meal. Most of the rest is absorbed by skeletal muscle. Because of the high Michaelis THE LIVER MAINTAINS THE BLOOD GLUCOSE s0060 constant (Km) of glucokinase for glucose, hepatic glu- LEVEL DURING FASTING cose utilization is controlled by substrate availability. Insulin induces the synthesis of glucokinase, but this In the fasting state, the liver has to spoon-feed the p0290 effect becomes maximal only after 2 or 3 days on a ­glucose-dependent tissues. The brain is the most de- high-carbohydrate diet. manding customer. It is the most aristocratic organ in p0285 The liver converts approximately two thirds of its the body; therefore, it requires a large share of the re- glucose allotment into glycogen after a meal. Most sources. Although the brain accounts for only 2% of Fatty acids Cytoplasm Fatty acids 2 Ketone bodies 4 1 β-Oxidation Acyl-CoA Acyl-CoA Acetyl-CoA Comp. by: Sathish Stage: Revises2 Chapter No.: 32 Title Name: Meisenberg (Carnitine) Glycerol- P Mitochondrion TCA 3 cycle VLDL Triglycerides, Phospholipids Page Number: 541 Date: 24/08/2016 Time: 09:10:58 f0035 Fig. 32.6 Alternative fates of fatty acids in the liver. The regulated steps are as follows: 1 Carnitine acyl transferase-1 is induced in the fasting state. It also is acutely inhibited by malonyl-CoA, the product of the acetyl-CoA carboxylase reaction when fatty acid biosynthesis is stimulated after a carbohydrate-rich meal. 2 Acetyl-CoA carboxylase is induced in the well-fed state. It is inhibited in the fasting state by high levels of acyl-CoA, low levels of citrate (direct allosteric effects), and a high glucagon/ insulin ratio (leading to phosphorylation and inactivation). 3 The tricarboxylic acid (TCA) cycle is inhibited when alternative sources supply ATP and NADH. Therefore a high rate of β-oxidation reduces its activity. 4 The ketogenic enzymes are induced during fasting. VLDL, Very-low-density lipoprotein. Meisenberg, 978-0-323-29616-8 To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s), editor(s), reviewer(s), Elsevier and typesetter SPi. It is not allowed to publish this proof online or in print. This proof copy is the copyright property of the publisher and is confidential until formal publication. These proofs may contain colour figures. Those figures may print black and white in the final printed book if a colour print product has not been planned. The colour figures will appear in colour in all electronic versions of this book. B978-0-323-29616-8.00032-3, 00032 542 METABOLISM adult body weight, it consumes approximately 20% of Other substrates are glycerol from adipose tissue and the total energy in the resting body (Table 32.5), and lactic acid from erythrocytes and other anaerobic cells up to 65% in young children. This large energy demand (Fig. 32.7). is covered from glucose under ordinary conditions and In most tissues, declining insulin levels induce a p0300 from glucose and ketone bodies during prolonged fast- switch from glucose oxidation to the oxidation of ing. The brain oxidizes 80 g of glucose per day in the fatty acids and ketone bodies during the transition well-fed state and 30 g during long-term fasting. from the well-fed to the fasting state. Consequently, p0295 Three to 4 hours after a meal, the liver becomes a net total body glucose consumption falls (Fig. 32.8). producer of glucose. After this time liver glycogen is the Only glucose-dependent tissues, including brain and major source of blood glucose until 12 to 16 hours after red blood cells, do not respond to insulin and keep the last meal, when gluconeogenesis becomes the ma- consuming glucose even during long-term fasting. jor and finally the only source. This switch is required The switch from glucose oxidation to fat oxidation because liver glycogen stores are almost completely ex- leads to a decline of the respiratory quotient (see hausted after 24 to 48 hours. More than half of the glu- Chapter 21) from about 0.9 after a mixed meal to cose produced in gluconeogenesis is from amino acids. slightly above 0.7 in the fasting state. VLDL Chylomicron remnants, Ketone Amino Glycerol Glucose Lactate Free fatty acids bodies acids Fatty acids Ketone Amino Glucose bodies acids + – Glucose 6- P + + – – + Acyl-CoA Acetyl-CoA Pyruvate Glycogen Triglycerides, Phospholipids Glycerol- P Lactate TCA cycle A VLDL Ketone Amino acids, Fatty acids Glycerol Glucose bodies Lactate Fatty acids Ketone Glucose bodies Glucose 6- P Glycogen Amino acids, Acyl-CoA Acetyl-CoA Pyruvate Lactate Triglycerides, Phospholipids Glycerol- P TCA cycle B f0040 Fig. 32.7 Metabolism of the yoyo dieter’s liver. A, After a meal. Pathways that are stimulated or inhibited by insulin are marked by + or -, respectively. B, Twelve hours after the last meal. Continued Meisenberg, 978-0-323-29616-8 To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s), editor(s), reviewer(s), Elsevier and typesetter SPi. It is not allowed to publish this proof online or in print. This proof copy is the copyright property of the publisher and is confidential until formal publication. These proofs may contain colour figures. Those figures may print black and white in the final printed book if a colour print product has not been planned. The colour figures will appear in colour in all electronic versions of this book. B978-0-323-29616-8.00032-3, 00032 Integration of Metabolism 543 Ketone Amino acids, VLDL Fatty acids Glycerol Glucose bodies Lactate Fatty acids Ketone Glucose bodies Glucose 6- P Glycogen Acyl-CoA Acetyl-CoA Pyruvate Amino acids, Lactate Triglycerides, Phospholipids Glycerol- P TCA cycle C VLDL Chylomicron remnants, Ketone Amino Glycerol Glucose Lactate Free fatty acids bodies acids Fatty acids Ketone Amino Glucose bodies acids Glucose 6- P Glycogen Acyl-CoA Acetyl-CoA Pyruvate Triglycerides, Phospholipids Lactate Glycerol- P TCA cycle D Fig. 32.7—cont’d C, Four days after the last meal. D, After the first good meal that follows 4 days of fasting. CoA, Coenzyme A; TCA, tricarboxylic acid; VLDL, very-low-density lipoprotein. Comp. by: Sathish Stage: Revises2 Chapter No.: 32 Title Name: Meisenberg Glucose used (g/h) 30 Page Number: 543 Date: 24/08/2016 Time: 09:10:58 Dietary glucose 20 Glycogenolysis (liver) Gluconeogenesis (liver) 10 4h 8h 12h 16h 20h 24h 2 3 4 5 6 7 Days f0045 Fig. 32.8 Total body glucose consumption after a meal and during fasting. Meisenberg, 978-0-323-29616-8 To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s), editor(s), reviewer(s), Elsevier and typesetter SPi. It is not allowed to publish this proof online or in print. This proof copy is the copyright property of the publisher and is confidential until formal publication. These proofs may contain colour figures. Those figures may print black and white in the final printed book if a colour print product has not been planned. The colour figures will appear in colour in all electronic versions of this book. B978-0-323-29616-8.00032-3, 00032 544 METABOLISM energy to synthesize 190 g of glucose from lactic acid s0065 KETONE BODIES PROVIDE LIPID-BASED without any need for the TCA cycle. ENERGY DURING FASTING Why does the liver convert fatty acids to ketone p0335 p0305 The fasting liver spoon-feeds the other tissues with bodies when carbohydrates are scarce? The main rea- ketone bodies as well as with glucose. In theory, both son is that the brain can oxidize ketone bodies but not carbohydrates and fatty acids can be converted into ke- fatty acids. Although the brain obtains almost all of its tone bodies through acetyl-CoA. Actually, however, the energy from glucose under ordinary conditions, it cov- liver forms ketone bodies from fatty acids during fasting ers up to two thirds of its energy needs from ketone but not from carbohydrates after a meal. bodies during prolonged fasting, when ketone body p0310 The liver has only a moderately high capacity for levels are very high. This reduces the need for gluco- glycolysis, and much of the glycolyzed glucose is con- neogenesis and thereby spares body protein. Liver me- verted into fat. Some is released into the blood as lactic tabolism in different nutritional states is summarized acid. This leaves very little for ketogenesis. However, in Fig. 32.7. the liver has a very high capacity for fatty acid oxida- The nutrient flows in the body change dramatically p0340 tion. Over a wide range of plasma levels, about 30% in different nutritional states. Fig. 32.9 shows the flow of incoming fatty acids is extracted and metabolized. of nutrients after different kinds of meals. Fig. 32.10 This means that hepatic fatty acid utilization is con- shows the changes during the transition from the well- trolled by substrate availability. It rises during fasting, fed state to prolonged fasting. The intestine provides for when adipose tissue supplies large amounts of free all of the body’s needs after a mixed meal, but adipose fatty acids. tissue and liver assume this role during fasting. p0315 The fasting liver has two options for the metabolism The refeeding of severely starved patients can be p0345 of these fatty acids (see Fig. 32.6). The first is esterifi- problematic. The levels of glycolytic enzymes in the cation into triglycerides and other lipids for export in liver are very low, and patients show profound carbohy- VLDL, which is released by the liver at all times. The drate intolerance. Therefore refeeding should be started second option is uptake into the mitochondrion fol- slowly, especially in advanced cases. lowed by β-oxidation. Carnitine-palmitoyl transferase-1, which controls the transport of long-chain fatty acids OBESITY IS COMMON IN ALL AFFLUENT s0070 into the mitochondrion, is induced by glucagon through COUNTRIES its second messenger cAMP and by fatty acids through the nuclear fatty acid receptor peroxisome proliferator-­ Obesity is not a disease, but the normal result of over- p0350 activated receptor-α (PPAR-α). eating. Its prevalence depends not only on the tastiness p0320 In the well-fed state, hepatic fatty acid oxidation is of the available food, but also on the definitions used. restrained because carnitine-palmitoyl transferase-1 The most commonly used measure, the body mass index is inhibited by malonyl-CoA, the product of the (BMI), is defined as follows: ­acetyl-CoA carboxylase reaction in fatty acid biosyn- BMI = Weight / Height2 thesis. During fasting, however, acetyl-CoA carbox- ylase is switched off by high levels of acyl-CoA, low A BMI of 18.5 to 24.9 kg/m2 is considered normal; levels of citrate, and a high glucagon/insulin ratio. a BMI between 25 and 29.9 signifies overweight, and a Malonyl-CoA is no longer formed, and an increased BMI of 30 or greater is defined as obesity. In 2010, 36% fraction of acyl-CoA is transported into the mitochon- of adults qualified as obese in the United States, 24% drion for β-oxidation. in Canada, and 26% in Britain. In the United States p0325 The acetyl-CoA that is formed in β-oxidation obesity-associated health problems make up approxi- ­ must be partitioned between the tricarboxylic acid mately 20% of the total health care costs. (TCA) cycle and ketogenesis. The activity of the TCA Body weight changes over the life span. In affluent p0360 cycle depends on the cell’s need for ATP. It is inhib- countries, women tend to gain weight between the ited by ATP and a high [NADH]/[NAD+] ratio (see ages of 20 and 60 years. Men tend to gain weight Chapter 22). β-­Oxidation produces NADH and, indi- more slowly from age 20 to age 50 years and to get rectly, ATP. By inhibiting the TCA cycle, NADH and thinner again after age 60. Lean body mass declines ATP divert a­ cetyl-CoA from TCA cycle oxidation to slowly in old age, so that those who maintain a con- ketogenesis. stant weight are gaining in fat. Without overeating, p0330 Ketogenesis amounts to an incomplete oxidation a slow decline of both muscle and fat is considered of fatty acids. Whereas the complete oxidation of one normal in old age. molecule of palmitoyl-CoA produces 131 molecules of Until the early years of the twentieth century, body p0365 ATP (see Chapter 25), its conversion to acetoacetate weight was related to social class, with rich people and β-hydroxybutyrate produces 35 and 23 molecules being heavier than poor people. Socioeconomic sta- of ATP, respectively. The conversion of 50 g of fatty ac- tus (SES) still is important today, but now poor peo- ids to acetoacetate during a hungry day supplies enough ple are fatter than the rich