-
1088
NPY/AgRP
POMC/CART
+
CHAPTER 27
Energy Metabolism:Integration and OrganSpecialization
1 Major Pathways and Strategies of EnergyMetabolism: A
Summary
2 Organ SpecializationA. BrainB. MuscleC. Adipose TissueD.
LiverE. Kidney
3 Metabolic Homeostasis: Regulation of Appetite,Energy
Expenditure, and Body WeightA. AMP-Dependent Protein Kinase Is the
Cells Fuel GaugeB. Adiponectin Regulates AMPK ActivityC. LeptinD.
InsulinE. Ghrelin and PYY336F. Hypothalamic Integration of Hormonal
SignalsG. Control of Energy Expenditure by Adaptive ThermogenesisH.
Did Leptin Evolve as a Thrifty Gene?
4 Metabolic AdaptationA. StarvationB. Diabetes Mellitus
At this point in our narrative we have studied all of the ma-jor
pathways of energy metabolism. Consequently, we arenow in a
position to consider how organisms, mammals inparticular,
orchestrate the metabolic symphony to meettheir energy needs.This
chapter therefore begins with a re-capitulation of the major
metabolic pathways and theircontrol systems, then considers how
these processes are ap-portioned among the various organs of the
body, and endswith a discussion of metabolic adaptation, including
howthe body maintains energy balance (homeostasis), how itdeals
with the metabolic challenges of starvation and obe-sity, and how
it responds to the loss of control resultingfrom diabetes
mellitus.
1 MAJOR PATHWAYS AND STRATEGIES OF ENERGYMETABOLISM: A
SUMMARY
Figure 27-1 indicates the interrelationships among the ma-jor
pathways involved in energy metabolism. Let us reviewthese pathways
and their control mechanisms.
1. Glycolysis (Chapter 17) The metabolic degrada-tion of glucose
begins with its conversion to two moleculesof pyruvate with the net
generation of two molecules eachof ATP and NADH. Under anaerobic
conditions, pyruvateis converted to lactate (or, in yeast, to
ethanol) so as to re-cycle the NADH. Under aerobic conditions,
however,when glycolysis serves to prepare glucose for further
oxi-dation, the NAD is regenerated through oxidative
phos-phorylation (see below). The flow of metabolites throughthe
glycolytic pathway is largely controlled by the activityof
phosphofructokinase (PFK).This enzyme is activated byAMP and ADP,
whose concentrations rise as the need forenergy metabolism
increases, and is inhibited by ATP andcitrate, whose concentrations
increase when the demandfor energy metabolism has slackened.
Citrate, a citric acidcycle intermediate, also inhibits PFK and
glycolysis whenaerobic metabolism takes over from anaerobic
metabo-lism, making glucose oxidation more efficient (the
Pasteureffect; Section 22-4C), and when fatty acid and/or
ketonebody oxidation (which are also aerobic pathways) areproviding
for energy needs (the glucosefatty acid orRandle cycle; Section
22-4Bb). PFK is also activated byfructose-2,6-bisphosphate, whose
concentration is regulatedby the levels of glucagon, epinephrine,
and norepinephrinethrough the intermediacy of cAMP (Section
18-3Fc). Liverand heart muscle F2,6P levels are regulated
oppositely: A[cAMP] increase causes an [F2,6P] decrease in liver
and an[F2,6P] increase in heart muscle. However, skeletal
muscle[F2,6P] does not respond to changes in [cAMP].
2. Gluconeogenesis (Section 23-1) Mammals can syn-thesize
glucose from a variety of precursors, includingpyruvate, lactate,
glycerol, and glucogenic amino acids (butnot fatty acids), through
pathways that occur mainly inliver and kidney. Many of these
precursors are converted tooxaloacetate which, in turn, is
converted to phospho-enolpyruvate and then, through a series of
reactions thatlargely reverse the path of glycolysis, to glucose.
The irre-versible steps of glycolysis, those catalyzed by PFK
andhexokinase, are bypassed in gluconeogenesis by
hydrolyticreactions catalyzed, respectively, by
fructose-1,6-bisphos-phatase (FBPase) and glucose-6-phosphatase.
FBPase andPFK may both be at least partially active
simultaneously,creating a substrate cycle.This cycle, and the
reciprocal reg-ulation of PFK and FBPase, are important in
regulatingboth the rate and direction of flux through glycolysis
and
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gluconeogenesis (Sections 17-4F and 23-1B). Fatty acid andketone
body oxidation can increase the rate of gluconeogen-esis in liver
by decreasing the concentration of F2,6P(Section 18-3Fc). This
occurs because the increased citrateconcentration accompanying
activation of the citric acidcycle during fatty acid oxidation
inhibits PFK-2 as well asPFK (Table 23-1). Phosphoenolpyruvate
carboxykinase(PEPCK) bypasses the third irreversible reaction of
glycol-ysis, that catalyzed by pyruvate kinase (PK), and is
con-trolled exclusively by long-term transcriptional
regulation.
3. Glycogen degradation and synthesis (Chapter 18)Glycogen, the
storage form of glucose in animals, occursmostly in liver and
muscle. Its conversion to glucose-6-phosphate (G6P) for entry into
glycolysis in muscle and itsconversion to glucose in liver is
catalyzed, in part, by glyco-gen phosphorylase, whereas the
opposing synthetic path-way is mediated by glycogen synthase. These
enzymes arereciprocally regulated through
phosphorylation/dephos-phorylation reactions as catalyzed by
amplifying cascadesthat respond to the levels of the hormones
glucagon andepinephrine through the intermediacy of cAMP, and
byinsulin (Sections 18-3E and 19-4F). The glucagoninsulinratio is
therefore a crucial factor in determining the rate anddirection of
glycogen metabolism.
4. Fatty acid degradation and synthesis (Sections 25-1through
25-5) Fatty acids are broken down in incrementsof C2 units through
oxidation to form acetyl-CoA. Theyare synthesized from this
compound via a separate path-way.The activity of the -oxidation
pathway varies with thefatty acid concentration.This, in turn,
depends on the activ-ity of hormone-sensitive triacylglycerol
lipase in adiposetissue that is stimulated, through cAMP-regulated
phos-phorylation/dephosphorylation reactions, by glucagon
andepinephrine but inhibited by insulin. The fatty acid synthe-sis
rate varies with the activity of acetyl-CoA carboxylase,
Section 27-1. Major Pathways and Strategies of Energy
Metabolism: A Summary 1089
glucose-6-phosphatase
fructose-1,6-bisphosphatase
phosphofructokinase
acetyl-CoA carboxylase
Glucose Glycogen
hexo-kinase
glycogensynthase
glycogenphosphorylase
Glucose-6-phosphate
pentosephosphatepathway
NADPH+
Ribose-5-phosphate
gluconeo-genesis glycolysis
Phosphoenol-pyruvate
pyruvatekinase
Pyruvatepyruvatedehydro-genase
Acetyl-CoA
Citricacidcycle
Glucogenicaminoacids
Oxaloacetate
NADH + FADH 2
ATP
Oxidativephosphorylation
ATP
Ketone bodies
Ketogenic amino acids
pyruvatecarboxylase
phosphoenol-pyruvate
carboxykinase
Lactate
NADHNAPDH
lactatedehydrogenase
Triacylglycerols
Fatty acids
hormone-sensitivetriacylglycerollipase
triacylglycerolsynthesis
oxidationfatty acidsynthesis
+ 2FADH
ATP
Figure 27-1 The major energy metabolism pathways.
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which is activated by citrate and insulin-dependent
de-phosphorylation, and inhibited by the pathway
productpalmitoyl-CoA and by cAMP- and AMP-dependent
phos-phorylation. Fatty acid synthesis is also subject to long-term
regulation through alterations in the rates of synthe-sis of the
enzymes mediating this process as stimulated byinsulin and
inhibited by fasting. The glucagoninsulin ratiois therefore of
prime importance in determining the rate anddirection of fatty acid
metabolism.
5. Citric acid cycle (Chapter 21) The citric acid cycleoxidizes
acetyl-CoA, the common degradation product ofglucose, fatty acids,
ketone bodies, and ketogenic aminoacids, to CO2 and H2O with the
concomitant production ofNADH and FADH2. Many glucogenic amino
acids can alsobe oxidized via the citric acid cycle through their
break-down, ultimately to pyruvate and then to acetyl-CoA,sometimes
via the cataplerosis (using up) of a citric acid cy-cle
intermediate (Section 21-5). The activities of the citricacid cycle
regulatory enzymes citrate synthase, isocitratedehydrogenase, and
-ketoglutarate dehydrogenase arecontrolled by substrate
availability and feedback inhibitionby cycle intermediates, NADH,
and ATP.
6. Oxidative phosphorylation (Chapter 22) This mito-chondrial
pathway oxidizes NADH and FADH2 to NAD
and FAD with the coupled synthesis of ATP. The rate ofoxidative
phosphorylation, which is tightly coordinatedwith the metabolic
fluxes through glycolysis and the citricacid cycle, is largely
dependent on the concentrations ofATP, ADP, and Pi, as well as
O2.
7. Pentose phosphate pathway (Section 23-4) Thispathway
functions to generate NADPH for use in reductivebiosynthesis, as
well as the nucleotide precursor ribose-5-phosphate, through the
oxidation of G6P. Its flux-generatingstep is catalyzed by
glucose-6-phosphate dehydrogenase,which is controlled by the level
of NADP. The ability ofenzymes to distinguish between NADH, which
is mainlyutilized in energy metabolism, and NADPH permits
energymetabolism and biosynthesis to be regulated
independently.
8. Amino acid degradation and synthesis (Sections 26-1through
26-5) Excess amino acids may be degraded to com-mon metabolic
intermediates. Most of these pathways beginwith an amino acids
transamination to its corresponding -keto acid with the eventual
transfer of the amino group tourea via the urea cycle. Leucine and
lysine are ketogenicamino acids in that they can be converted only
to acetyl-CoAor acetoacetate and hence cannot be glucose
precursors.Theother amino acids are glucogenic in that they may be,
at leastin part, converted to one of the glucose precursors
pyruvate,oxaloacetate, -ketoglutarate, succinyl-CoA, or
fumarate.Five amino acids are both ketogenic and glucogenic.
Essen-tial amino acids are those that an animal cannot synthesize
it-self; they must be obtained from plant and microbial
sources.Nonessential amino acids can be synthesized by animals
uti-lizing preformed amino groups via pathways that are gener-ally
simpler than those synthesizing essential amino acids.
Two compounds lie at the crossroads of the foregoingmetabolic
pathways: acetyl-CoA and pyruvate (Fig. 27-1).
Acetyl-CoA is the common degradation product of mostmetabolic
fuels, including polysaccharides, lipids, and pro-teins. Its acetyl
group may be oxidized to CO2 and H2O viathe citric acid cycle and
oxidative phosphorylation or usedto synthesize fatty acids.
Pyruvate is the product of glycoly-sis, the dehydrogenation of
lactate, and the breakdown ofcertain glucogenic amino acids. It may
be oxidatively decar-boxylated to yield acetyl-CoA, thereby
committing itsatoms either to oxidation or to the biosynthesis of
fattyacids.Alternatively, it may be carboxylated via the
pyruvatecarboxylase reaction to form oxaloacetate, which, in
turn,either replenishes citric acid cycle intermediates or
entersgluconeogenesis via phosphoenolpyruvate, thereby bypass-ing
an irreversible step in glycolysis. Pyruvate is therefore
aprecursor of several amino acids as well as of glucose.
The foregoing pathways occur in specific cellular com-partments.
Glycolysis, glycogen synthesis and degradation,fatty acid
synthesis, and the pentose phosphate pathwayare largely or entirely
cytosolically based, whereas fattyacid degradation, the citric acid
cycle, and oxidative phos-phorylation occur in the mitochondrion.
Different phasesof gluconeogenesis and amino acid degradation occur
ineach of these compartments. The flow of metabolites
acrosscompartment membranes is mediated, in most cases, by
spe-cific carriers that are also subject to regulation.
The enormous number of enzymatic reactions that simul-taneously
occur in every cell (Fig. 16-1) must be coordinatedand strictly
controlled to meet the cells needs. Such regula-tion occurs on many
levels. Intercellular communicationsregulating metabolism occur via
certain hormones, includingepinephrine, norepinephrine, glucagon,
and insulin, as well asthrough a series of steroid hormones known
as glucocorti-coids (whose effects are discussed in Section
19-1Ga). Thesehormonal signals trigger a variety of cellular
responses, in-cluding the synthesis of second messengers such as
cAMP inthe short term and the modulation of protein synthesis
ratesin the long term. On the molecular level, enzymatic
reactionrates are controlled by
phosphorylation/dephosphorylationvia amplifying reaction cascades,
by allosteric responses tothe presence of effectors, which are
usually precursors orproducts of the reaction pathway being
controlled, and bysubstrate availability. The regulatory machinery
of opposingcatabolic and anabolic pathways is generally arranged
suchthat these pathways are reciprocally regulated.
2 ORGAN SPECIALIZATION
Different organs have different metabolic functions
andcapabilities. In this section we consider how the specialneeds
of the mammalian body organs are met and howtheir metabolic
capabilities are coordinated to meet theseneeds. In particular, we
discuss brain, muscle, adipose tis-sue, liver, and kidney (Fig.
27-2).
A. Brain
Brain tissue has a remarkably high respiration rate. For
in-stance, the human brain constitutes only 2% of the adult
1090 Chapter 27. Energy Metabolism: Integration and Organ
Specialization
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body mass but is responsible for 20% of its resting
O2consumption. This consumption, moreover, is independentof the
state of mental activity; it varies little between sleepand the
intense concentration required of, say, the study ofbiochemistry.
Most of the brains energy production servesto power the plasma
membrane (NaK)ATPase (Sec-tion 20-3A), which maintains the membrane
potentialrequired for nerve impulse transmission (Section 20-5).
Infact, the respiration of brain slices is over 50% reduced bythe
(NaK)ATPase inhibitor ouabain (Section 20-3Af).
Under usual conditions, glucose serves as the brainsonly fuel
(although, with extended fasting, the brain gradu-ally switches to
ketone bodies; Section 27-4A). Indeed,since brain cells store very
little glycogen, they require a
steady supply of glucose from the blood. A blood
glucoseconcentration of less than half of the normal value of 5
mMresults in brain dysfunction. Levels much below this, forexample,
caused by severe insulin overdose, result in coma,irreversible
damage, and ultimately death. One of thelivers major functions,
therefore, is to maintain the bloodglucose level (Sections 18-3F
and 27-2D).
B. Muscle
Muscles major fuels are glucose from glycogen, fatty acids,and
ketone bodies. Rested, well-fed muscle, in contrast tobrain,
synthesizes a glycogen store comprising 1 to 2% ofits mass. The
glycogen serves muscle as a readily available
Section 27-2. Organ Specialization 1091
Ketone bodies
Ketone bodies
Ketone bodies
Ketone bodies
NH3
Glutamine-Ketoglutarate
Glucose
Glucose
Glucose
Glycogen
Urea
Kidney
LactateUrea
Pyruvate
Glucose
Glycogen
Pyruvate
Proteins
Proteins
Amino acids
Amino acids
Acetyl-CoA
Fatty acids
Fatty acids
Triacylglycerols
Glycerol
Liver
CO2 + H2O
CO2 + H2O CO2 + H2O
Brain
Adipose tissue
Lactate Alanine + Glutamine
Muscle
Glucose
Fatty acids
Glycerol
+Triacylglycerols
Figure 27-2 The metabolic interrelationships among brain,adipose
tissue, muscle, liver, and kidney. The red-outlined arrowsindicate
pathways that predominate in the well-fed state when
glucose, amino acids, and fatty acids are directly available
fromthe intestines.
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fuel depot since it can be rapidly converted to G6P for en-try
into glycolysis (Section 18-1).
Muscle cannot export glucose because it lacks
glucose-6-phosphatase. Nevertheless, muscle serves the body as
anenergy reservoir because, during the fasting state, itsproteins
are degraded to amino acids, many of which areconverted to
pyruvate, which in turn, is transaminated toalanine. The alanine is
then exported via the bloodstreamto the liver, which transaminates
it back to pyruvate, aglucose precursor. This process is known as
the glucosealanine cycle (Section 26-1Ad).
Since muscle does not participate in gluconeogenesis,it lacks
the machinery that regulates this process in suchgluconeogenic
organs as liver and kidney. Muscle doesnot have receptors for
glucagon, which, it will be recalled,stimulates an increase in
blood glucose levels (Section18-3F). However, muscle possesses
epinephrine receptors (-adrenergic receptors; Section 19-1F), which
throughthe intermediacy of cAMP control the
phosphorylation/dephosphorylation cascade system that regulates
glyco-gen breakdown and synthesis (Section 18-3). This is thesame
cascade system that controls the competition be-tween glycolysis
and gluconeogenesis in liver in responseto glucagon.
Heart muscle and skeletal muscle contain differentisozymes of
PFK-2/FBPase-2. The heart muscle isozyme iscontrolled by
phosphorylation oppositely to that in liver,whereas skeletal muscle
PFK-2/FBPase-2 is not controlledby phosphorylation at all (Section
18-3Fc). Thus the con-centration of F2,6P rises in heart muscle but
falls in liver inresponse to an increase in [cAMP]. Moreover the
muscleisozyme of pyruvate kinase, which, it will be recalled,
cat-alyzes the final step of glycolysis, is not subject to
phospho-rylation/dephosphorylation as is the liver isozyme
(Section23-1Ba).Thus, whereas an increase in liver cAMP
stimulatesglycogen breakdown and gluconeogenesis, resulting in
glu-cose export, an increase in heart muscle cAMP activatesglycogen
breakdown and glycolysis, resulting in glucoseconsumption.
Consequently, epinephrine, which preparesthe organism for action
(fight or flight), acts independentlyof glucagon which, acting
reciprocally with insulin, regulatesthe general level of blood
glucose.
a. Muscle Contraction Is Anaerobic UnderConditions of High
ExertionMuscle contraction is driven by ATP hydrolysis (Section
35-3Bb) and is therefore ultimately dependent on respira-tion.
Skeletal muscle at rest utilizes 30% of the O2 con-sumed by the
human body.A muscles respiration rate mayincrease in response to a
heavy workload by as much as25-fold. Yet, its rate of ATP
hydrolysis can increase by amuch greater amount. The ATP is
initially regenerated bythe reaction of ADP with phosphocreatine as
catalyzed bycreatine kinase (Section 16-4Cd):
(phosphocreatine is resynthesized in resting muscle by
thereversal of this reaction). Under conditions of maximumexertion,
however, such as occurs in a sprint, a muscle has
Phosphocreatine ADP creatine ATP
only an 5-s supply of phosphocreatine. It must then shiftto ATP
production via glycolysis of G6P resulting fromglycogen breakdown,
a process whose maximum fluxgreatly exceeds those of the citric
acid cycle and oxidativephosphorylation. Much of this G6P is
therefore degradedanaerobically to lactate (Section 17-3A) which,
in the Coricycle (Section 23-1C), is exported via the bloodstream
tothe liver, where it is reconverted to glucose through
gluco-neogenesis. Gluconeogenesis requires ATP generated
byoxidative phosphorylation. Muscles thereby shift much oftheir
respiratory burden to the liver and consequently alsodelay the
O2-consumption process, a phenomenon knownas oxygen debt.The source
of ATP during exercise of vary-ing duration is summarized in Fig.
27-3.
b. Muscle Fatigue Has a Protective FunctionMuscle fatigue,
defined as the inability of a muscle to
maintain a given power output, occurs in 20 s under con-ditions
of maximum exertion. Such fatigue is not caused bythe exhaustion of
the muscles glycogen supply. Rather, itmay result from glycolytic
proton generation that can dropthe intramuscular pH from its
resting value of 7.0 to as lowas 6.4 (fatigue does not, as is
widely believed, result fromthe buildup of lactate itself, as is
demonstrated by the ob-servation that muscles can sustain a large
power output un-der high lactate concentrations if the pH is
maintainednear 7.0). Nevertheless, how acidification might cause
mus-cle fatigue is unclear. Two other proposed causes for mus-cle
fatigue are (1) the increased [Pi] arising largely from the
1092 Chapter 27. Energy Metabolism: Integration and Organ
Specialization
Figure 27-3 Source of ATP during exercise in humans. Thesupply
of endogenous ATP is extended for a few seconds byphosphocreatine,
after which anaerobic glycolysis generates ATP.The shift from
anaerobic to aerobic metabolism (oxidativephosphorylation) occurs
after about 90 s, or slightly later intrained athletes. [Adapted
from McArdle, W.D., Katch, F.I., andKatch, V.L., Exercise
Physiology, 2nd ed., Lea & Febiger (1986),p. 348.]
High jumpPower liftShot putTennis serve
Anaerobic systems
ATP
SprintsFootball line play
Phospho-creatine
200400 m race100 m swim
Glycolysis
Racebeyond500 m
Oxidative phosphorylation
0 4 s 10 s 1.5 min
Duration of activity
3 min
Aerobic systems
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utilization of ATP may precipitate Ca2 as calcium phos-phate
(which is highly insoluble), thereby decreasingcontractile force
(muscle contraction is triggered by therelease of Ca2 ion; Section
35-3Cb); and (2) the K ionknown to be released from contracting
muscle cells mayresult in their depolarization (Section 20-5Ba) and
hence areduction in their contraction. Whatever its cause(s),
itseems likely that muscle fatigue is an adaptation that pre-vents
muscle cells from committing suicide by exhaustingtheir ATP supply
(recall that glycolysis and other ATP-generating pathways must be
primed by ATP).
c. The Heart Is a Largely Aerobic OrganThe heart is a muscular
organ but one that must main-
tain continuous rather than intermittent activity. Thusheart
muscle, except for short periods of extreme exertion,relies
entirely on aerobic metabolism. It is therefore richlyendowed with
mitochondria; they comprise up to 40% ofits cytoplasmic space,
whereas some types of skeletal mus-cle are nearly devoid of
mitochondria. The heart canmetabolize fatty acids, ketone bodies,
glucose, pyruvate,and lactate. Fatty acids are the resting hearts
fuel of choicebut, on the imposition of a heavy workload, the
heartgreatly increases its rate of consumption of glucose, whichis
derived mostly from its relatively limited glycogen store.
C. Adipose Tissue
Adipose tissue, which consists of cells known as adipocytes(Fig.
12-2), is widely distributed about the body but occursmost
prominently under the skin, in the abdominal cavity,in skeletal
muscle, around blood vessels, and in mammarygland. The adipose
tissue of a normal 70-kg man contains15 kg of fat. This amount
represents some 590,000 kJ ofenergy (141,000 dieters Calories),
which is sufficient tomaintain life for 3 months. Yet, adipose
tissue is by nomeans just a passive storage depot. In fact, it is
second inimportance only to liver in the maintenance of
metabolichomeostasis (Section 27-3).
Adipose tissue obtains most of its fatty acids from theliver or
from the diet as described in Section 25-1. Fattyacids are
activated by the formation of the correspondingfatty acyl-CoA and
then esterified with glycerol-3-phosphate to form the stored
triacylglycerols (Section 25-4F).The glycerol-3-phosphate arises
from the reductionof dihydroxyacetone phosphate, which must be
glycolyti-cally generated from glucose or gluconeogenically
gener-ated from pyruvate or oxaloacetate (a process called
glyc-eroneogenesis; Section 25-4Fa) because adipocytes lack akinase
that phosphorylates endogenous glycerol.
Adipocytes hydrolyze triacylglycerols to fatty acids andglycerol
in response to the levels of glucagon, epinephrine,and insulin
through a reaction catalyzed by hormone-sensitive triacylglycerol
lipase (Section 25-5). If glycerol-3-phosphate is abundant, many of
the fatty acids so formedare reesterified to triacylglycerols.
Indeed, the averageturnover time for triacylglycerols in adipocytes
is only a fewdays. If, however, glycerol-3-phosphate is in short
supply,the fatty acids are released into the bloodstream. The rate
of
glucose uptake by adipocytes, which is regulated by insulin
aswell as by glucose availability, is therefore also an
importantfactor in triacylglycerol formation and mobilization.
How-ever, glycerol-3-phosphate is also produced via
glyceroneo-genesis under the control of PEPCK, allowing
triacylglyc-erol turnover even when glucose concentration is
low.
a. Obesity Results from Aberrant Metabolic ControlThe human body
regulates glycogen and protein levels
within relatively narrow limits, but fat reserves, which aremuch
larger, can become enormous. The accumulation offatty acids as
triacylglycerols in adipose tissue is largely aresult of excess fat
or carbohydrate intake compared to en-ergy expenditure. Fat
synthesis from carbohydrates occurswhen the carbohydrate intake is
high enough that glycogenstores, to which excess carbohydrate is
normally directed,approach their maximum capacity.
Obesity is one of the major health-related problems inindustrial
countries. An estimated 30% of adults in theUnited States are obese
(are at least 20% above their de-sirable weights) and another 35%
are overweight. Mostobese people find it inordinately difficult to
lose weight or,having done so, to keep it off. Yet most animals,
includinghumans, tend to have stable weights; that is, if they
aregiven free access to food, they eat just enough to maintainthis
so-called set point weight.The nature of the regulatorymachinery
that controls the set point, which in obese indi-viduals seems to
be aberrantly high, is just beginning tocome to light (see Section
27-3).
Formerly grossly obese individuals who have lost atleast 100 kg
to reach their normal weights exhibit some ofthe metabolic symptoms
of starvation: they are obsessedwith food, have low heart rates,
are cold intolerant, and re-quire 25% less caloric intake than
normal individuals ofsimilar heights and weights. In both normal
and obese indi-viduals, some 50% of the fatty acids liberated by
the hy-drolysis of triacylglycerols are reesterified before they
canleave the adipocytes. In formerly obese subjects,
thisreesterification rate is only 35 to 40%, a level similar to
thatobserved in normal individuals after a several day fast.Thefat
cells in normal and obese individuals, moreover, are ofroughly the
same size; obese people just have more ofthem. In fact, adipocyte
precursor cells from massivelyobese individuals proliferate
excessively in tissue culturecompared to those from normal or even
moderately obesesubjects (adipocytes themselves do not replicate).
Sincefat cells, once gained, are never lost, this suggests
thatadipocytes, although highly elastic in size, tend to maintaina
certain fixed volume and in doing so influence the metab-olism and
thus the appetite. This insight, unfortunately, hasnot yet led to a
method for lowering the set points of indi-viduals with a tendency
toward obesity.
D. Liver
The liver is the bodys central metabolic clearinghouse. It
func-tions to maintain the proper levels of nutrients in the
bloodfor use by the brain, muscles, and other tissues. The liveris
uniquely situated to carry out this task because all the
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nutrients absorbed by the intestines except fatty acids are
re-leased into the portal vein,which drains directly into the
liver.
One of the livers major functions is to act as a blood glu-cose
buffer. It does so by taking up or releasing glucose inresponse to
the levels of glucagon, epinephrine, and insulinas well as to the
concentration of glucose itself. After acarbohydrate-containing
meal, when the blood glucoseconcentration reaches 6 mM, the liver
takes up glucoseby converting it to G6P. The process is catalyzed
by gluco-kinase (Section 18-3Fa), which differs from hexokinase,
theanalogous glycolytic enzyme in other cells, in that glucoki-nase
has a much lower affinity for glucose (glucokinasereaches
half-maximal velocity at 5 mM glucose vs 0.1 mM glucose for
hexokinase) and is not inhibited byG6P. Liver cells, in contrast to
muscle and adipose cells, arepermeable to glucose, and thus insulin
has no direct effecton their glucose uptake. Since the blood
glucose concentra-tion is normally less than glucokinases KM, the
rate ofglucose phosphorylation in the liver is more or less
propor-tional to the blood glucose concentration.The other
intesti-nally absorbed sugars, mostly fructose, galactose, and
man-nose, are also converted to G6P in the liver (Section
17-5).After an overnight fast, the blood glucose level drops to4
mM. The liver keeps it from dropping below this levelby releasing
glucose into the blood as is described below. Inaddition, lactate,
the product of anaerobic glucose metabo-lism in the muscle, is
taken up by the liver for use in gluco-neogenesis and lipogenesis
as well as in oxidative phospho-rylation (the Cori cycle; Section
23-1C). Alanine producedin the muscle is taken up by the liver and
converted topyruvate for gluconeogenesis as well (the
glucosealaninecycle; Section 26-1Ad).
a. The Fate of Glucose-6-Phosphate Varies with Metabolic
RequirementsG6P is at the crossroads of carbohydrate metabolism;
it
can have several alternative fates depending on the
glucosedemand (Fig. 27-1):
1. G6P can be converted to glucose by the action
ofglucose-6-phosphatase for transport via the bloodstream tothe
peripheral organs.
2. G6P can be converted to glycogen (Section 18-2)when the bodys
demand for glucose is low. Yet, increasedglucose demand, as
signaled by higher levels of glucagonand/or epinephrine, reverses
this process (Section 18-1).
3. G6P can be converted to acetyl-CoA via glycolysisand the
action of pyruvate dehydrogenase (Chapter 17 andSection 21-2). Most
of this glucose-derived acetyl-CoA isused in the synthesis of fatty
acids (Section 25-4), whosefate is described below, and in the
synthesis of phospho-lipids (Section 25-8) and cholesterol (Section
25-6A).Cholesterol, in turn, is a precursor of bile salts, which
areproduced by the liver (Section 25-6C) for use as emulsify-ing
agents in the intestinal digestion and absorption of fats(Section
25-1).
4. G6P can be degraded via the pentose phosphatepathway (Section
23-4) to generate the NADPH required
for fatty acid biosynthesis and the livers many
otherbiosynthetic functions, as well as ribose-5-phosphate (R5P)for
nucleotide biosynthesis (Sections 28-1A and 28-2A).
b. The Liver Can Synthesize or Degrade TriacylglycerolsFatty
acids are also subject to alternative metabolic
fates in the liver (Fig. 27-1):
1. When the demand for metabolic fuels is high, fattyacids are
degraded to acetyl-CoA and then to ketonebodies (Section 25-3) for
export via the bloodstream to theperipheral tissues.
2. When the demand for metabolic fuels is low, fattyacids are
used to synthesize triacylglycerols that are se-creted into the
bloodstream as VLDL for uptake byadipose tissue. Fatty acids may
also be incorporated intophospholipids (Section 25-8).
Since the rate of fatty acid oxidation varies only withfatty
acid concentration (Section 25-5), fatty acids pro-duced by the
liver might be expected to be subject to reox-idation before they
can be exported. Such a futile cycle isprevented by the
compartmentalization of fatty acid oxida-tion in the mitochondrion
and fatty acid synthesis in the cy-tosol. Carnitine
palmitoyltransferase I, a component of thesystem that transports
fatty acids into the mitochondrion(Section 25-2B), is inhibited by
malonyl-CoA, the key in-termediate in fatty acid biosynthesis
(Section 25-4A).Hence, when the demand for metabolic fuels is low
so thatfatty acids are being synthesized, they cannot enter the
mi-tochondrion for conversion to acetyl-CoA. Rather, thelivers
biosynthetic demand for acetyl-CoA is met throughthe degradation of
glucose.
When the demand for metabolic fuel rises so as to in-hibit fatty
acid biosynthesis, however, fatty acids are trans-ported into the
liver mitochondria for conversion to ke-tone bodies. Under such
conditions of low blood glucoseconcentrations, glucokinase has
reduced activity so thatthere is net glucose export (there is,
however, always a fu-tile cycle between the reactions catalyzed by
glucokinaseand glucose-6-phosphatase; Section 18-3Fb). The liver
can-not use ketone bodies for its own metabolic purposes be-cause
liver cells lack 3-ketoacyl-CoA transferase (Section25-3). Fatty
acids rather than glucose or ketone bodies aretherefore the livers
major acetyl-CoA source under condi-tions of high metabolic demand.
The liver generates itsATP from this acetyl-CoA through the citric
acid cycle andoxidative phosphorylation. The aerobic oxidation of
fattyacids inhibits glucose utilization since activation of
thecitric acid cycle and oxidative phosphorylation increasesthe
concentration of citrate, which inhibits glycolysis
(theglucosefatty acid or Randle cycle; Section 22-4Bb).
c. Amino Acids Are Important Metabolic FuelsThe liver degrades
amino acids to a variety of metabolic
intermediates (Section 26-3). These pathways mostly beginwith
amino acid transamination to yield the corresponding-keto acid
(Section 26-1A) with the amino group being
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ultimately converted, via the urea cycle (Section 26-2), to
thesubsequently excreted urea. Glucogenic amino acids canbe
converted in this manner to pyruvate or citric acid
cycleintermediates such as oxaloacetate and are thereby
gluco-neogenic precursors (Section 23-1). Ketogenic amino
acids,many of which are also glucogenic, may be converted to
ke-tone bodies.
The livers glycogen store is insufficient to supply thebodys
glucose needs for more than 6 h after a meal.Afterthat, glucose is
supplied through gluconeogenesis fromamino acids arising mostly
from muscle protein degradationto alanine (the glucosealanine
cycle; Section 26-1Ad) andglutamine (the transport form of ammonia;
Section 26-1B).Thus proteins, in addition to their structural and
functionalroles, are important fuel resources. (Animals cannot
convertfat to glucose because they lack a pathway for the net
con-version of acetyl-CoA to oxaloacetate; Section 23-2).
d. The Liver Is the Bodys Major Metabolic Processing UnitThe
liver has numerous specialized biochemical func-
tions in addition to those already mentioned. Prominentamong
them are the synthesis of blood plasma proteins, thedegradation of
porphyrins (Section 26-4A) and nucleicacid bases (Section 28-4),
the storage of iron, and thedetoxification of biologically active
substances such asdrugs, poisons, and hormones by a variety of
oxidation(e.g., by cytochromes P450; Section 15-4Bc), reduction,
hy-drolysis, conjugation, and methylation reactions.
E. Kidney
The kidney functions to filter out the waste product ureafrom
the blood and concentrate it for excretion, to recoverimportant
metabolites such as glucose, and to maintain thebloods pH. Blood pH
is maintained by regenerating de-pleted blood buffers such as
bicarbonate (lost by the exha-lation of CO2) and by removing for
excretion excess H
to-gether with the conjugate bases of excess metabolic acidssuch
the ketone bodies acetoacetate and -hydroxybu-tyrate. Phosphate,
the major buffer in urine for moderateacid excretion, is
accompanied by equivalent quantities ofcations such as Na and K.
However, large losses of Na
and K would upset the bodys electrolyte balance, so onthe
production of large amounts of acids such as lactic acidor ketone
bodies, the kidney produces NH4
to aid in theexcretion of the excess H (utilizing Cl or the
conjugatebase of a metabolic acid as the counterion). This NH4
isgenerated from glutamine, which is converted first to
gluta-mate and then to -ketoglutarate by glutaminase and glu-tamate
dehydrogenase. The overall reaction is
The -ketoglutarate is converted to malate by the citricacid
cycle and then is exported from the mitochondrionand converted
either to pyruvate, which is oxidized com-pletely to CO2, or via
oxaloacetate to PEP and then to glu-cose via gluconeogenesis. High
fat diets, which produce
Glutamine -ketoglutarate 2NH4
high blood concentrations of free fatty acids and ketonebodies
and hence high acidic loads, cause -ketoglutarateto be converted
completely to CO2, and then to bicarbon-ate, thereby increasing the
bloods buffering capacity. Dur-ing starvation, the -ketoglutarate
enters gluconeogenesis,to the extent that the kidneys generate as
much as 50% ofthe bodys glucose supply.
3 METABOLIC HOMEOSTASIS:REGULATION OF APPETITE,
ENERGYEXPENDITURE, AND BODY WEIGHT
When a normal animal overeats, the resulting additionalfat
somehow signals the brain to induce the animal to eatless and to
expend more energy. Conversely, the loss of fatstimulates increased
eating until the lost fat is replaced.Evidently, animals have a
lipostat that can keep theamount of body fat constant to within 1%
over many years.At least a portion of the lipostat resides in the
hypothala-mus (a part of the brain that hormonally controls
numer-ous physiological functions; Section 19-1H), since damag-ing
it can yield a grossly obese animal.
Despite this obvious set of controls in animals, there hasbeen
an explosion of obesity in many industrial nations. Ithas, in fact,
become a world health problem, leading to dia-betes and heart
disease. As a result of numerous studies inrecent years,
researchers have been able to outline themechanisms involved in
metabolic homeostasis, the bal-ance between energy influx and
energy expenditure, and toidentify some of the irregularities that
lead to obesity.A va-riety of mutant strains of rodents have been
generated thatcause obesity. The study of these mutants has
resulted inthe identification of several hormones that act in a
coordi-nated manner to regulate appetite.
A. AMP-Dependent Protein Kinase Is the Cells Fuel Gauge
All of the metabolic pathways discussed in Section 27-1
areaffected in one way or another by the need for ATP, as is
in-dicated by the cells AMP-to-ATP ratio (Section 17-4Fd).Several
enzymes are either activated or inhibited allosteri-cally by AMP,
and several others are phosphorylated byAMP-dependent protein
kinase (AMPK), a major regula-tor of metabolic homeostasis. AMPK
activates metabolicbreakdown pathways that generate ATP while
inhibitingbiosynthetic pathways so as to conserve ATP for more
vitalprocesses. AMPK is an heterotrimer found in all eu-karyotic
organisms from yeast to humans. The subunitcontains a Ser/Thr
protein kinase domain, and the sub-unit contains sites for
allosteric activation by AMP andinhibition by ATP. Like other
protein kinases, AMPKskinase domain must be phosphorylated for
activity. Bindingof AMP to the subunit causes a conformational
changethat exposes Thr 172 in the activation loop of the
subunit,promoting its phosphorylation and increasing its activity
atleast 100-fold. AMP can activate the phosphorylated en-zyme up to
5-fold more. There are two isoforms of the
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subunit, two of the subunit, and three of the subunit,giving
rise to 12 possible heterotrimeric combinations, withsplice
variants yielding further diversity. The major kinasethat
phosphorylates AMPK is named LKB1. The knockoutof LKB1 in mouse
liver results in the loss of the phospho-rylated form of AMPK.
a. AMPK Activates Glycolysis in Ischemic Cardiac MuscleAMPKs
targets include the heart isozyme of the bi-
functional enzyme PFK-2/FBPase-2, which controls
thefructose-2,6-bisphosphate (F2,6P) concentration (Section18-3Fc).
The phosphorylation of this isozyme activates thePFK-2 activity,
increasing [F2,6P], which in turn activatesPFK-1, the
rate-determining enzyme of glycolysis (Section17-4Fb).
Consequently, in ischemic (blood-starved) heartmuscle cells, which
receive insufficient oxygen for oxida-tive phosphorylation to
maintain adequate concentrationsof ATP, the resulting AMP buildup
causes the cells toswitch to anaerobic glycolysis for ATP
production.
b. AMPK Inhibits Lipogenesis, CholesterolSynthesis, and
Gluconeogenesis in LiverAMPK-mediated phosphorylation also inhibits
acetyl-
CoA carboxylase (ACC), which catalyzes the first committedstep
of fatty acid synthesis (Section 25-4B), and
hydroxy-methylglutaryl-CoA reductase (HMG-CoA reductase),which
catalyzes the rate-determining step in cholesterolbiosynthesis
(Section 25-6Aa).Activated AMPK inhibits glu-coneogenesis in a more
complicated way: It phosphorylatesand thereby inactivates the
transcriptional coactivatorTORC2 (for transducer of regulated CREB
activity-2), whichin concert with the transcriptional activator
CREB, wouldotherwise induce the transcription of the gene encoding
PEPcarboxykinase (PEPCK), the enzyme that catalyzes the
rate-determining step of gluconeogenesis (Sections 23-1Af and
23-1Bb). Consequently, when the rate of ATP production is
inad-equate, these biosynthetic pathways are turned off,
therebyconserving ATP for more vital cellular functions.
c. AMPK Promotes Fatty Acid Oxidation andGlucose Uptake but
Inhibits Glycogen Synthesis in Skeletal MuscleThe inhibition of ACC
results in a decrease in the con-
centration of malonyl-CoA, the starting material for fattyacid
biosynthesis. Malonyl-CoA has an additional role,however. It is an
inhibitor of carnitine palmitoyltransferaseI (Section 25-2B), which
is required to transfer cytosolicpalmitoyl-CoA into mitochondria
for oxidation. The de-crease in malonyl-CoA concentration therefore
allowsmore palmitoyl-CoA to be oxidized. AMPK also increasesthe
recruitment of GLUT4 to muscle cell plasma mem-branes (Section
20-2Ec), as well as stimulating its expres-sion, thus facilitating
the insulin-independent entry of glu-cose into these cells. In
addition, AMPK inhibits glycogensynthase (which catalyzes the
rate-limiting reaction inglycogen synthesis; Section 18-3B). In
fact, the subunit ofAMPK has a glycogen-binding domain that
presumably re-cruits AMPK to the vicinity of glycogen synthase.
d. AMPK Inhibits Fatty Acid Synthesis and Lipolysis in
AdipocytesAMPK inhibits fatty acid synthesis in adipocytes by
phosphorylating ACC as described above. Moreover,AMPK
phosphorylates hormone-sensitive triacylglycerollipase in adipose
tissue (Section 25-5). This phosphoryla-tion inhibits rather than
activates the enzyme, in part bypreventing the relocation of the
enzyme to the lipiddroplet, the cellular location of lipolysis. As
a result, fewertriacylglycerol molecules are broken down so that
fewerfatty acids are exported to the bloodstream. This
latterprocess seems paradoxical (fatty acid oxidation wouldhelp
relieve an ATP deficit), although it has been specu-lated that it
prevents the cellular buildup of fatty acids totoxic levels. The
major effects of AMPK activation onglucose and lipid metabolism in
liver, skeletal muscle, heartmuscle, and adipose tissue are
diagrammed in Fig. 27-4.
B. Adiponectin Regulates AMPK Activity
Adiponectin is a 247-residue protein hormone, secreted
ex-clusively by adipocytes, that helps regulate energy homeo-stasis
and glucose and lipid metabolism by controllingAMPK activity. Its
monomers consist of an N-terminal col-lagenlike domain and a
C-terminal globular domain.Adiponectin occurs in the bloodstream in
several forms: alow molecular weight (LMW) trimer formed by the
coilingof its collagenlike domains into a triple helix (Section
8-2Ba) as well as hexamers (MMW) and multimers (HMW)that form
disulfide cross-linked bouquets (Fig. 27-5). In ad-dition, globular
adiponectin, formed by the cleavage of thecollagenlike domain to
release globular monomers, occursin lower concentrations.
The binding of adiponectin to adiponectin receptors,which occur
on the surfaces of both liver and muscle cells,acts to increase the
phosphorylation and activity of AMPK.This, as we have seen (Section
27-3A), inhibits gluconeo-genesis and stimulates fatty acid
oxidation in liver and stimu-lates glucose uptake and glucose and
fatty acid oxidation inmuscle. All of these effects act to increase
insulin sensitiv-ity, in part because adiponectin and insulin
elicit similar re-sponses in tissues such as liver. Decreased
adiponectin isassociated with insulin resistance (Section 27-4B).
Para-doxically, the blood concentration of adiponectin, which
issecreted by adipocytes, decreases with increased amountsof
adipose tissue. This may be because increased adiposetissue is also
associated with increased production of tumornecrosis factor-
(TNF-), a cytokine that decreases boththe expression and secretion
of adiponectin from adiposetissue (Section 19-3Db).
C. Leptin
Two of the genes whose mutations cause obesity in miceare known
as obese (ob) and diabetes (db; the wild-typegenes are designated
OB and DB). Homozygotes fordefects in either of these recessive
genes, ob/ob or db/db,are grossly obese and have nearly identical
phenotypes(Fig. 27-6). Indeed, the way in which these
phenotypes
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S-S
HMW
MMW
LMW
S-S
were distinguished was by surgically linking the circulationof a
mutant mouse to that of a normal (OB/OB) mouse, aphenomenon named
parabiosis. ob/ob mice so linked
exhibit normalization of body weight and reduced foodintake,
whereas db/db mice do not do so. This suggests thatob/ob mice are
deficient in a circulating factor that regu-lates appetite and
metabolism, whereas db/db mice aredefective in the receptor for
this circulating factor.
Section 27-3. Metabolic Homeostasis: Regulation of Appetite,
Energy Expenditure, and Body Weight 1097
Figure 27-5 Adiponectin trimers, hexamers, and multimers.These
complexes are referred to as low molecular weight(LMW), medium
molecular weight (MMW), and high molecularweight (HMW) forms.
[After Kadowaki, T., and Yamauchi, T.,Endocr. Rev. 26, 439
(2005).]
Figure 27-6 Normal (OB/OB, left) and obese (ob/ob, right)mice.
[Courtesy of Richard D. Palmiter, University ofWashington.]
Figure 27-4 Major effects of AMP-activated protein kinase(AMPK)
on glucose and lipid metabolism in liver, muscle, andadipose
tissue. In skeletal muscle, AMPK stimulates glucose andfatty acid
oxidation while inhibiting glycogen synthesis. In heartmuscle, AMPK
stimulates glycolysis. In liver, AMPK inhibits
Skeletal Muscle
Heart Muscle
Fat
Liver
Glucose
Glucose
Acetyl-CoA
Fatty acid
Glycogen
Glucose
Lactate
Fatty acid
Glucose
Fatty acid
Triglyceride
Glucose
Stimulated by AMPKStimulated by AMPKStimulated by AMPK
Fatty acid
Pyruvate
Pyruvate
Cholesterol CO2
CO2
Inhibited by AMPKInhibited by AMPK
lipid biosynthesis and gluconeogenesis while activating fatty
acidoxidation. In adipose tissue,AMPK inhibits fatty acid
biosynthesis,lipolysis, and fatty acid export. [After Towler, M.C.
and Hardie,D.G., Circ. Res. 100, 328 (2007).]
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The mouse OB gene encodes a 146-residue monomericprotein named
leptin (Greek: leptos, thin; Fig. 27-7) thathas no apparent
homology with proteins of known se-quence. Leptin, which was
discovered by Jeffrey Friedman,is expressed only by adipocytes,
which in doing so appearto inform the brain of how much fat the
body carries. Thus,injecting leptin into ob/ob mice causes them to
eat less andto lose weight. In fact, leptin-treated ob/ob mice on a
re-stricted diet lost 50% more weight than untreated ob/obmice on
the same diet, which suggests that reduced food in-take alone is
insufficient to account for leptin-inducedweight loss. Leptin
appears to control energy expenditureas well.
Leptin injection has no effect on db/db mice. The leptinreceptor
gene was identified by making a cDNA libraryfrom mouse brain tissue
that specifically bound leptin andthen identifying a
receptor-expressing clone by its ability tobind leptin (gene
cloning techniques are discussed in Sec-tion 5-5). This gene, which
has been shown to be the DBgene, encodes a protein named OB-R (for
OB receptor)that appears to have a single transmembrane segment
andan extracellular domain that resembles the receptors forcertain
cytokines (proteins that regulate the differentia-tion,
proliferation, and activities of various blood cells; Sec-tion
19-3Eb).
OB-R protein, which was discovered by Louis Tartaglia,has at
least six alternatively spliced forms that appear to beexpressed in
a tissue-specific manner (alternative genesplicing is discussed in
Section 31-4Am). In normal mice,the hypothalamus expresses high
levels of a splice variantof OB-R that has a 302-residue
cytoplasmic segment. How-ever, in db/db mice, this segment has an
abnormal splicesite that truncates it to only 34 residues, which
almost cer-tainly renders this OB-R variant unable to transmit
leptinsignals. Thus, it appears that leptins weight-controlling
ef-fects are mediated by signal transduction resulting from
itsbinding to the OB-R protein in the hypothalamus.
Human leptin is 84% identical in sequence to that ofmice. The
use of a radioimmunoassay (Section 19-1A) tomeasure the serum
levels of leptin in normal-weight andobese humans established that
in both groups serum leptinconcentrations increase with their
percentage of body fatas does the ob mRNA content of their
adipocytes. More-over, after obese individuals had lost weight,
their serumleptin concentrations and adipocyte ob mRNA content
de-clined. This suggests that most obese persons produce
suf-ficient amounts of leptin but have developed leptin
resist-ance. Since leptin must cross the bloodbrain barrier inorder
to exert its effects on the hypothalamus, it has beensuggested that
this crossing is somehow saturatable, thuslimiting the
concentration of leptin in the brain. The highconcentration of
leptin in obese individuals is not withoutaffect, however. OB-R is
also expressed in peripheral tis-sues where leptin has been shown
to function as well.Whilenot preventing obesity, the hormone has
been shown to di-rectly stimulate the oxidation of fatty acids as
well as to in-hibit the accumulation of lipids in non-adipose
tissue. Itdoes so by activating AMP-dependent protein kinase(AMPK),
which in turn phosphorylates and thereby inacti-
vates acetyl-CoA carboxylase (ACC). This reduces themalonyl-CoA
concentration, thereby decreasing its inhibi-tion of carnitine
palmitoyltransferase I, which then trans-ports fatty acyl-CoA into
the mitochondrion for oxidation(Section 25-5). We discuss the
function of leptin in periph-eral tissues in Section 27-3H.
A small minority of obese individuals have been foundto be
leptin deficient in a manner similar to ob/ob mice.Two grossly
obese children who are members of the samehighly consanguineous
(descended from the same ances-tors) family (they are cousins and
both sets of parents arecousins) have been shown to be homozygous
for a defec-tive OB gene.The children, at the ages of 8 and 2 years
old,respectively, weighed 86 and 29 kg and were noted to
haveremarkably large appetites.Their OB genes have a deletionof a
single guanine nucleotide in codon 133, thereby caus-ing a
frameshift mutation that, it is likely, renders the
1098 Chapter 27. Energy Metabolism: Integration and Organ
Specialization
Figure 27-7 X-ray structure of human leptin-E100. Thismutant
form of leptin (W100E) has comparable biologicalactivity to the
wild-type protein but crystallizes more readily. Theprotein, which
is colored in rainbow order from its N-terminus(blue) to its
C-terminus (red), forms a four-helix bundle, as domany protein
growth factors (e.g., human growth hormone;Fig. 19-10). Residues 25
to 38 are not visible in the X-raystructure. [Based on an X-ray
structure by Faming Zhang, EliLilly & Co., Indianapolis,
Indiana. PDBid 1AX8.]
See Interactive Exercise 27.
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mutant leptin biologically inactive. Moreover, their leptinserum
levels were only 10% of normal. Leptin injectionshave relieved
their symptoms.
D. Insulin
We have discussed the insulin signaling cascade (Section19-4F)
and the role of insulin in peripheral tissues such asmuscle and
adipose tissue in stimulating the uptake of glu-cose (Fig. 20-11)
and its storage as glycogen (Section 18-3)or fat (Section 25-5).
Insulin receptors also occur in the hy-pothalamus. Consequently,
the infusion of insulin into ratswith insulin-deficient diabetes
inhibits food intake, revers-ing the overeating behavior
characteristic of the disease.Knock-out mice have been developed
with a central nervoussystemspecific disruption of the insulin
receptor gene.Thesemice have no alteration in brain development or
survivalbut become obese, with increased body fat, increased
leptinlevels, increased serum triacylglycerol, and the
elevatedplasma insulin levels characteristic of insulin
resistance(Section 27-4B). Evidently, insulin also plays a role in
theneuronal regulation of food intake and body weight.As wediscuss
in Section 27-3F, insulin and leptin both act throughreceptors in
the hypothalamus to decrease food intake.
E. Ghrelin and PYY336
a. Ghrelin and PYY336 Act as Short-Term Regulators of
AppetiteGhrelin, which was discovered by Masayasu Kojima and
Kenji Kanagawa, is an appetite-stimulating gastric peptidethat
is secreted by the empty stomach.This 28-residue pep-tide was first
discovered and named for its function as agrowth hormonereleasing
peptide (ghrelin is an abbrevia-tion for growth-hormone-release).
Octanoylation of itsSer 3 is required for activity.
Injection of ghrelin has been shown to induce
adiposity(increased adipose tissue) in rodents by stimulating an
in-crease in food intake while reducing fat utilization. In hu-mans
in states of positive energy balance such as obesity orhigh caloric
intake, circulating ghrelin levels are decreased,whereas during
fasting, circulating ghrelin levels increase.
PYY336
is a peptide secreted by the gastrointestinal tract in
propor-tion to the caloric intake of a meal, which acts to inhibit
fur-ther food intake. Both rodents and humans have beenshown to
respond to the presence of this peptide by decreas-ing their food
intake for up to 12 hours. Human subjects re-ceiving a 90-minute
infusion of PYY336 ate only 1500 kcal of
IKPEAPGE DASPEELNRY YASLRHYLNL VTRQRY36
Human PYY336
3020103
GSXFLSPEHQ RVQQRKESKK PPAKLQPR20 2810
Human ghrelinX = Ser modified with n-octanoic acid
Section 27-3. Metabolic Homeostasis: Regulation of Appetite,
Energy Expenditure, and Body Weight 1099
food during the next 24-hour period, whereas those receiv-ing
saline controls ate 2200 kcal during the same period.
F. Hypothalamic Integration of Hormonal Signals
a. Neurons of the Arcuate Nucleus Region of the Hypothalamus
Integrate and Transmit Hunger SignalsAbout half of the length of
the hypothalamus is taken
up by the arcuate nucleus, a collection of neuronal cellbodies
consisting of two cell types: the NPY/AgRP celltype and the
POMC/CART cell type. These cell types arenamed after the
neuropeptides they secrete. NeuropeptideY (NPY)
is a potent stimulator of food intake and an inhibitor ofenergy
expenditure, as is Agouti related peptide
(AgRP).Pro-opiomelanocortin (POMC) is post-translationallyprocessed
in the hypothalamus to release -melanocytestimulating hormone
(-MSH; Section 34-3C). Cocaineand amphetamine-regulated transcript
(CART) and -MSHare both inhibitors of food intake and stimulators
of energyexpenditure.
The balance of the secretions from these two cell types
iscontrolled by leptin, insulin, ghrelin, and PYY336 (Fig.
27-8).Leptin and insulin signal satiety and therefore
decreaseappetite by diffusing across the bloodbrain barrier tothe
arcuate nucleus, where they stimulate POMC/CARTneurons to produce
CART and -MSH, while inhibitingthe production of NPY from NPY/AgRP
neurons. Leptinreceptors act through the JAKSTAT signal
transductionpathway (Section 19-3Eb). Ghrelin has receptors
onNPY/AgRP neurons that stimulate the secretion of NPYand AgRP to
increase appetite. Interestingly, PYY336, apeptide that is
homologous to NPY, binds specifically toNPY receptor subtype Y2R on
NPY/AgRP neurons. Thissubtype is an inhibitory receptor, however,
so binding ofPYY336 causes a decrease in secretion from
NPY/AgRPneurons. The integrated stimuli of all these secretions
fromthe arcuate nucleus control appetite.
G. Control of Energy Expenditure by Adaptive Thermogenesis
The energy content of food is utilized by an organism ei-ther in
the performance of work or the generation of heat.Excess energy is
stored as glycogen or fat for future use. Inwell-balanced
individuals, the storage of excess fuel re-mains constant over many
years. However, when energyconsumed is consistently greater than
energy expended,obesity results. The body has several mechanisms
forpreventing obesity. One of them, as discussed above, isappetite
control. The other is diet-induced thermogenesis,a form of adaptive
thermogenesis (heat production in
YPSKPDNPGE DAPAEDMARY YSALRHYINL ITRQRYNH236
Neuropeptide YThe C-terminal carboxyl is amidated
3020101
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1100 Chapter 27. Energy Metabolism: Integration and Organ
Specialization
the opening of a proton channel, called uncoupling pro-tein-1
(UCP1) or thermogenin, in the inner mitochondrialmembrane. The
opening of UCP1 discharges the protongradient across the inner
mitochondrial membrane, thusuncoupling electron transport from ATP
production. Theenergy that would otherwise have been used to drive
ATPsynthesis is thereby released as heat.
Although metabolic measurements in adult humansclearly
demonstrate that an increase in energy intakecauses an increase in
metabolic rate and thermogenesis, thecause of this increase is
unclear. Adult humans have littlebrown adipose tissue. However,
skeletal muscle represents
response to environmental stress). We have previously dis-cussed
adaptive thermogenesis in response to cold, whichoccurs in rodents
and newborn humans through the uncou-pling of oxidative
phosphorylation in brown adipose tissue(Section 22-3Da).The
mechanism of this thermogenesis in-volves the release of
norepinephrine from the brain in re-sponse to cold, its binding to
-adrenergic receptors onbrown adipose tissue inducing an increase
in [cAMP],which in turn initiates an enzymatic phosphorylation
cas-cade that activates hormone-sensitive triacylglycerol li-pase.
The resulting increase in the concentration of freefatty acids
provides fuel for oxidation as well as inducing
Neuron
NPY/AgRP
POMC/CART
Foodintake
EnergyexpenditureArcuate
nucleus
Fat tissue
Colon
Ghrelin
PYY3-36Insulin
+
+
Leptin
Pancreas
Stomach
NPY receptor Y1R
NPY/PYY3-36receptor Y2R
Ghrelin receptor
MSH receptor (MC4R)(blocked by AgRP)
Leptin receptoror insulin receptor
MSH receptor (MC3R)
Figure 27-8 Hormones that control the appetite. Leptin
andinsulin (bottom) circulate in the blood at
concentrationsproportional to body-fat mass. They decrease appetite
byinhibiting NPY/AgRP neurons (center) while
stimulatingmelanocortin-producing neurons in the arcuate nucleus
region ofthe hypothalamus. NPY and AgRP increase the appetite,
andmelanocortins decrease the appetite, via other neurons
(top).Activation of NPY/AgRP-expressing neurons inhibits
melanocortin-producing neurons. The gastric hormone
ghrelinstimulates appetite by activating the
NPY/AgRP-expressingneurons. PYY336, released from the
gastrointestinal tract,inhibits NPY/AgRP-expressing neurons and
thereby decreasesthe appetite. PYY336 works in part through the
autoinhibitoryNPY receptor subtype Y2R. [After Schwartz, M.W. and
Morton,G.J., Nature 418, 596 (2002).]
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-
up to 40% of their total body weight and has high mito-chondrial
capacity. Homologs of UCP1 have been identi-fied: UCP2 occurs in
many tissues including white adiposetissue, whereas UCP3 occurs in
brown adipose tissue, whiteadipose tissue, and muscle. Leptin has
been shown to up-regulate UCP2. However, it has yet to be
demonstratedthat UCP3 in muscle participates in diet-induced
thermo-genesis. ATP-hydrolyzing substrate cycles such as that
be-tween fatty acids and triacylglycerol in adipose tissue
(Sec-tion 27-2C) may also be involved.
H. Did Leptin Evolve as a Thrifty Gene?
The unusual behavior of leptin, which serves to controlweight in
normal-weight individuals while its concentrationcontinues to climb
without apparent effect in obese individu-als, has led to the
proposal that leptin evolved as a thriftygene.In hunter-gatherer
societies, it was a distinct advantageto be able to survive
intermittent famines. In order to do this,fat must be stored in
adipose tissue in times of plenty, makingshort-term obesity
advantageous. However, the accumula-tion of fatty acids and lipids
in non-adipose tissue results incoronary artery disease, insulin
resistance, and diabetes (Sec-tion 27-4B). Leptin, by directly
stimulating the oxidation offatty acids as well as inhibiting the
accumulation of lipids innon-adipose tissue, is thought to protect
against these dis-eases during short-term obesity, thereby
providing an evolu-tionary advantage. However, in recent times in
industrializednations, the unprecedented availability of food and
lack offamine has made obesity a long-term rather than a short-term
condition, which is a liability rather than a benefit.
4 METABOLIC ADAPTATION
In this section we consider the bodys responses to
twometabolically abnormal situations: (1) starvation and (2)
thedisease diabetes mellitus.
A. Starvation
Glucose is the metabolite of choice of both brain andworking
muscle. Yet, the body stores less than a days sup-ply of
carbohydrate (Table 27-1).Thus, the low blood sugarcaused by even
an overnight fast results, through an in-crease in glucagon
secretion and a decrease in insulin se-cretion, in the mobilization
of fatty acids from adipose tis-sue (Section 25-5). The diminished
insulin level alsoinhibits glucose uptake by muscle tissue. Muscles
thereforeswitch from glucose to fatty acid metabolism for
energyproduction. The brain, however, still remains heavily
de-pendent on glucose.
In animals, glucose cannot be synthesized from fattyacids. This
is because neither pyruvate nor oxaloacetate,the precursors of
glucose in gluconeogenesis (Section 23-1),can be synthesized from
acetyl-CoA (the oxaloacetate inthe citric acid cycle is derived
from acetyl-CoA but thecyclic nature of this process requires that
the oxaloacetatebe consumed as fast as it is synthesized; Section
21-1A).
During starvation, glucose must therefore be synthesizedfrom the
glycerol product of triacylglycerol breakdownand, more importantly,
from the amino acids derived fromthe proteolytic degradation of
proteins, the major source ofwhich is muscle. Thus, after a 40-hour
fast, gluconeogenesissupplies 96% of the glucose produced by the
liver. How-ever, the continued breakdown of muscle during
prolongedstarvation would ensure that this process became
irre-versible since a large muscle mass is essential for an
animalto move about in search of food. The organism must there-fore
make alternate metabolic arrangements.
After several days of starvation, gluconeogenesis has sodepleted
the livers oxaloacetate supply that this organsability to
metabolize acetyl-CoA via the citric acid cycle isgreatly
diminished. Rather, the liver converts the acetyl-CoA to ketone
bodies (Section 25-3), which it releases intothe blood. The brain
gradually adapts to using ketone bod-ies as fuel through the
synthesis of the appropriate en-zymes: After a 3-day fast, only
about one-third of thebrains energy requirements are satisfied by
ketone bodiesbut after 40 days of starvation, 70% of its energy
needsare so met. The rate of muscle breakdown during pro-longed
starvation consequently decreases to 25% of itsrate after a
several-day fast. The survival time of a starvingindividual is
therefore much more dependent on the size ofhis or her fat reserves
than it is on his or her muscle mass.Indeed, highly obese
individuals can survive for over a yearwithout eating (and have
occasionally done so in clinicallysupervised weight reduction
programs).
a. Caloric Restriction May Increase LongevityCaloric restriction
is a modified form of starvation
whereby energy intake is reduced 3040%, while micronu-trient
(vitamin and mineral) levels are maintained. Rodentskept on such a
diet live up to 50% longer than rodents onnormal diets and exhibit
fewer of the debilitating symptomsof old age.The life spans of a
large range of organisms fromyeast to primates are similarly
extended. Considerableresearch effort is being expended to
determine the bio-chemical basis of these observations.
Section 27-4. Metabolic Adaptation 1101
Table 27-1 Fuel Reserves for a Normal 70-kg Man
Fuel Mass (kg) Caloriesa
Tissues
Fat (adipose triacyglycerols) 15 141,000
Protein (mainly muscle) 6 24,000
Glycogen (muscle) 0.150 600
Glycogen (liver) 0.075 300
Circulating fuels
Glucose (extracellular fluid) 0.020 80
Free fatty acids (plasma) 0.0003 3
Triacylglycerols (plasma) 0.003 30
Total 166,000aOne (dieters) Calorie 1 kcal 4.184 kJ.
Source: Cahill, G.F., Jr., New Engl. J. Med. 282, 669
(1970).
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B. Diabetes Mellitus
The polypeptide hormone insulin acts mainly on muscle,liver, and
adipose tissue cells to stimulate the synthesis ofglycogen, fats,
and proteins while inhibiting the breakdownof these metabolic
fuels. In addition, insulin stimulates theuptake of glucose by most
cells, with the notable exceptionof brain and liver cells. Together
with glucagon, which haslargely opposite effects, insulin acts to
maintain the properlevel of blood glucose.
In the disease diabetes mellitus, which is the third
leadingcause of death in the United States after heart disease
andcancer, insulin either is not secreted in sufficient amounts
ordoes not efficiently stimulate its target cells. As a
conse-quence, blood glucose levels become so elevated that
theglucose spills over into the urine, providing a
convenientdiagnostic test for the disease. Yet, despite these high
bloodglucose levels, cells starve since insulin-stimulated
glucoseentry into cells is impaired. Triacylglycerol hydrolysis,
fattyacid oxidation, gluconeogenesis, and ketone body formationare
accelerated and, in a condition termed ketoacidosis, ke-tone body
levels in the blood become abnormally high. Sinceketone bodies are
acids, their high concentration puts astrain on the buffering
capacity of the blood and on the kid-ney, which controls blood pH
by excreting the excess H
into the urine (Section 27-2E). This unusually high excessH
excretion is accompanied by NH4
, Na, K, Pi, and H2Oexcretion, causing severe dehydration (which
compoundsthe dehydration resulting from the osmotic effect of the
highglucose concentration in the blood; excessive thirst is a
clas-sic symptom of diabetes) and a decrease in blood
volumeultimately life-threatening situations.
There are two major forms of diabetes mellitus:
1. Insulin-dependent, type 1, or juvenile-onset
diabetesmellitus, which most often strikes suddenly in
childhood.
2. Noninsulin-dependent, type 2, or maturity-onsetdiabetes
mellitus, which usually develops rather graduallyafter the age of
40.
a. Insulin-Dependent Diabetes Is Caused by aDeficiency of
Pancreatic CellsIn insulin-dependent (type 1) diabetes mellitus,
insulin
is absent or nearly so because the pancreas lacks or
hasdefective cells. This condition results, in genetically
sus-ceptible individuals (see below), from an autoimmune re-sponse
that selectively destroys their cells. Individualswith
insulin-dependent diabetes, as Frederick Banting andGeorge Best
first demonstrated in 1921, require dailyinsulin injections to
survive and must follow carefully bal-anced diet and exercise
regimens. Their life spans are,nevertheless, reduced by up to
one-third as a result of de-generative complications such as kidney
malfunction,nerve impairment, and cardiovascular disease, which
ap-parently arise from the imprecise metabolic control pro-vided by
periodic insulin injections. The hyperglycemia(high blood
[glucose]) of diabetes mellitus also leads toblindness through
retinal degeneration and the glucosyla-tion of lens proteins, which
causes cataracts (Fig. 27-9).
Perhaps newly developed systems that monitor blood glu-cose
levels and continuously deliver insulin in the requiredamounts will
rectify this situation.
The usually rapid onset of the symptoms of insulin-dependent
diabetes had suggested that the autoimmune at-tack on the
pancreatic cells responsible for this disease isone of short
duration. Typically, however, the diseasebrews for several years as
the aberrantly aroused immunesystem slowly destroys the cells. Only
when 80% of thesecells have been eliminated do the classic symptoms
of dia-betes suddenly emerge. Consequently, one of the most
suc-cessful treatments for insulin-dependent diabetes is a
-celltransplant, a procedure that became possible with the
devel-opment of relatively benign immunosuppressive drugs.
Why does the immune system attack the pancreatic cells? It has
long been known that certain alleles (geneticvariants) of the Class
II major histocompatibility complex(MHC) proteins are particularly
common in insulin-dependent diabetics [MHC proteins are highly
polymorphic(variable within a species) immune system components
towhich cell-generated antigens such as viral proteins mustbind in
order to be recognized as foreign; Sections 35-2Aaand 35-2E]. It is
thought that autoimmunity against cells isinduced in a susceptible
individual by a foreign antigen, per-haps a virus, which
immunologically resembles some cellcomponent. The Class II MHC
protein that binds this anti-gen does so with such tenacity that it
stimulates the immunesystem to launch an unusually vigorous and
prolonged at-tack on the antigen. Some of the activated immune
systemcells eventually make their way to the pancreas, where
theyinitiate an attack on the cells due to the close resemblanceof
the cell component to the foreign antigen.
b. Noninsulin-Dependent Diabetes Is Characterized by Insulin
Resistance as Well as Impaired Insulin
SecretionNoninsulin-dependent (type 2) diabetes mellitus
(NIDDM), which accounts for over 90% of the diagnosedcases of
diabetes and affects 18% of the population over65 years of age,
usually occurs in obese individuals with agenetic predisposition
for this condition (although onethat differs from that associated
with insulin-dependent
1102 Chapter 27. Energy Metabolism: Integration and Organ
Specialization
Figure 27-9 Photo of a diabetic cataract. The accumulation
ofglucose in the lens leads to swelling and precipitation of
lensproteins. The resulting opacification causes blurred vision
andultimately complete loss of sight. [ Sue Ford/Photo
Researchers.]
JWCL281_c27_1088-1106.qxd 4/21/10 9:42 AM Page 1102
-
diabetes). These individuals may have normal or evengreatly
elevated insulin levels. Their symptoms arise frominsulin
resistance, an apparent lack of sensitivity to insulinin normally
insulin-responsive cells.
The hyperglycemia that accompanies insulin resistanceinduces the
pancreatic cells to increase their productionof insulin. Yet the
high basal level of insulin secretion di-minishes the ability of
the cells to respond to further in-creases in blood glucose.
Consequently, the hyperglycemiaand its attendant complications tend
to worsen over time.
A small percentage of cases of type II diabetes resultfrom
mutations in the insulin receptor that affect itsinsulin-binding
ability or tyrosine kinase activity. However,a clear genetic cause
has not been identified in the vast ma-jority of cases. It is
therefore likely that many factors play arole in the development of
this disease. For example, the in-creased insulin production
resulting from overeating mayeventually suppress the synthesis of
insulin receptors. Thishypothesis accounts for the observation that
diet alone isoften sufficient to control this type of diabetes.
Insulin resistance, which may precede NIDDM by asmuch as 10 to
20 years, appears to be caused by an inter-ruption in the insulin
signaling pathway (Section 19-4F).Gerald Shulman has proposed that
this interruption iscaused by a Ser/Thr kinase cascade that
phosphorylates
proteins known as insulin receptor substrates (IRSs; Sec-tion
19-3Cg) so as to decrease their ability to be phospho-rylated on
their Tyr residues by activated insulin receptor.Tyrosine
phosphorylation is required for IRS activationand communication
with phosphoinositide 3-kinase (PI3K;Section 19-4D), which
subsequently activates the translo-cation of GLUT4-containing
vesicles to the cell surface forincreased glucose transport into
cells (Section 20-2Ec).Theoriginal Ser/Thr kinase cascade is
triggered by the activa-tion of an isoform of protein kinase C
(PKC; Section 19-4C)caused by an increase in fatty acyl-CoA,
diacylglycerol, andceramides (Section 12-1D) resulting from
elevated freefatty acids (Fig. 27-10). The failure to activate IRSs
de-creases the cells response to insulin (Fig. 27-11).
c. Substances That Activate AMPK Attenuate theSymptoms of
Noninsulin-Dependent DiabetesOther treatments for
noninsulin-dependent diabetes
are drugs such as metformin and the
thiazolidinediones(TZDs),
which decrease insulin resistance by either suppressingglucose
release by the liver (metformin) or promoting
A thiazolidinedione (TZD)
Metformin
O
NH
O
R
S
H3C
NH2
NHNH
NHN
H3C
Section 27-4. Metabolic Adaptation 1103
Figure 27-10 The mechanism through which high concentra-tions of
free fatty acids cause insulin resistance. Elevated concen-trations
of free fatty acids in the blood diffuse into muscle cellswhere
they are converted to fatty acyl-CoA, diacylglycerols,
andceramides. These lipotoxic substances activate an isoform
ofprotein kinase C (PKC), triggering a Ser/Thr kinase cascade
thatresults in the phosphorylation of IRS-1 and IRS-2.
Thisphosphorylation inhibits the Tyr phosphorylation required
fortransmission of the insulin signal, thereby decreasing
theactivation of PI3K, which decreases the rate of fusion
ofGLUT4-containing vesicles with the plasma membrane andhence the
amount of glucose entering the cell. [Modified fromShulman, G.I.,
J. Clin. Invest. 106, 173 (2000).]
Figure 27-11 Twenty-four-hour plasma glucose profiles in nor-mal
and noninsulin-dependent diabetic subjects. The basal levelof
glucose and the peaks following meals are higher in thediabetic
individuals. [After Bell, G.I., Pilkis, S.J., Weber, I.T.,
andPolonsky, K.S., Annu. Rev. Physiol. 58, 178 (1996).]
PlasmaGlucose
Glucose
Insulin receptor
Insulin
IRS-1/IRS-2 Ser/Thr phosphorylation
PI3K
IRS-1/IRS-2 Tyr phosphorylation
Fatty acyl-CoA,diacylglycerols,ceramides
Fatty acids
Ser/Thr kinasecascade
PKC
GLUT4
240 480 720 960 1200 14400 0
20
Pla
sma
[Glu
cose
] (m
M)
Time (min)
Non-insulin-dependentdiabetes
Normal
breakfast
15
10
5
lunch dinner
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insulin-stimulated glucose disposal in muscle (TZDs).These drugs
act by increasing AMPK activity but by differ-ent mechanisms.TZDs
cause a large increase in the AMP toATP ratio in muscle cells, with
the expected concomitant in-crease in AMPK phosphorylation and
activity. Metformin,however, stimulates LKB1 to phosphorylate and
hence ac-tivate AMPK (LKB1 knockout mice are insensitive to
met-formin). In both cases, the increase in AMPK activity
de-creases gluconeogenesis in liver and increases
glucoseutilization in muscle (Fig. 27-4). In addition, the TZDs
de-crease insulin resistance by binding to and activating
atranscription factor known as a peroxisome proliferatoractivated
receptor (PPAR), primarily in adipose tissue.Among other things,
PPAR activation induces the synthe-sis of adiponectin (Section
27-3B), which leads to an in-crease in AMPK activity. In adipose
tissue, AMPK actionleads to a decrease in lipolysis and fatty acid
export, de-creasing the concentration of free fatty acids in the
bloodand therefore decreasing insulin resistance (see above).
Intriguingly, Ronald Evans has shown that transgenicmice
expressing an activated form of PPAR in their skele-tal muscles can
run around twice the distance of wild-typemice and are resistant to
weight gain, even on a high fatdiet.This activated PPAR induces an
increase in the num-ber of the aerobic and hence fatty
acidoxidizing slow-twitch (Type I) muscle fibers (Section 17-3Ca)
relative tothe largely anaerobic and hence less energy-efficient
fast-twitch (Type II) muscle fibers.
Rodent adipocytes secrete a 108-residue polypeptidehormone
called resistin. The hormone is named for its abil-ity to block the
action of insulin on adipocytes. In fact, re-sistin production is
decreased by TZDs, a phenomenonthat led to the discovery of
resistin. Overproduction ofresistin was proposed to contribute to
the development ofnoninsulin-dependent diabetes. An interesting
differencebetween rodents and humans is that in humans, resistin
isproduced by macrophages, a divergence whose evolution-ary and
functional implications are unclear.
d. Obesity Is a Contributing Factor in Metabolic
SyndromeMetabolic syndrome is a disturbance in metabolism
characterized by insulin resistance, inflammation, and
apredisposition to several disorders including type 2 dia-betes,
hypertension, and atherosclerosis. These disordersare accompanied
by an increase in coronary heart disease.Obesity, physical
inactivity, and possibly genetic determi-nants have been implicated
in its occurrence, which affectsas many as 65 million people in the
United States alone.Exercise, calorie/weight reduction,
adiponectin, leptin,metformin, and TZDs have all been successfully
used totreat metabolic syndrome. Similarly, the PPAR agonistknown
as GW1516
GW1516
F3C
CH3N
S S O COOH
1104 Chapter 27. Energy Metabolism: Integration and Organ
Specialization
alleviates the symptoms of metabolic syndrome in obesemen,
probably by stimulating fatty acid oxidation.
Evans has shown that GW1516 greatly increases exer-cise
endurance in mice, particularly when it is administeredtogether
with the AMPK agonist 5-aminoimidazole-4-carboxamide ribotide
[AICAR];
which is also a product of histidine biosynthesis
(Section26-5Be) and an intermediate in purine
ribonucleotidebiosynthesis (Section 28-1A)]. This treatment mimics
theeffects of the expression of activated PPAR, which sug-gests
that the administration of GW1516 and AICAR canconfer some of the
benefits of exercise without actually ex-ercising. Indeed, the
World Anti-Doping Agency hasplaced these compounds on the list of
performance-enhancing drugs that athletes are forbidden from
taking.
e. DNA Chip Technology Permits the IntegratedStudy of Metabolic
RegulationOur ability to understand the integrated nature of
me-
tabolism and its genetic regulation in health and diseasehas
taken a giant step forward with the advent of DNAchips
(microarrays; Section 7-6B). For example, RonaldKahn has used this
technology to study the genetic basis ofthe metabolic abnormalities
underlying both obesity anddiabetes. To do so, he isolated the mRNA
from the skeletalmuscle of normal, diabetic, and insulin-treated
diabeticmice and reverse-transcribed it to cDNA (Section
5-5Fa),which was then hydridized to oligonucleotide microarraysthat
represented 14,288 mouse genes. Thereby, 129 up-regulated and 106
down-regulated genes were identified indiabetic mice. Not
surprisingly, the expression of the mRNAsencoding enzymes of the
fatty acid -oxidation pathwaywere increased, whereas those for
GLUT4, glucokinase,the E1 component of the pyruvate dehydrogenase
multien-zyme complex, and the subunits of all four
mitochondrialelectron-transport chain complexes were coordinately
de-creased. Intriguingly, only about half of these changes ingene
expression could be reversed by insulin treatment.Thus, the
post-genomic era will almost certainly witness anexplosion in our
knowledge of metabolic regulation thatshould yield major health
benefits. Nevertheless, our abilityto sensibly interpret this huge
influx of information mayprove to be the greatest challenge.
NC CH
CC
O
N
CH2O2O3P
H HH H
OH OH
O
H2N
H2N
5-Aminoimidazole-4-carboxamide ribotide (AICAR)
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References 1105
1 Major Pathways and Strategies of Energy Metabolism:A Summary
The complex network of processes involved inenergy metabolism are
distributed among different compart-ments within cells and in
different organs of the body. Theseprocesses function to generate
ATP on demand, to generateand store glucose, triacylglycerols, and
proteins in times ofplenty for use when needed, and to keep the
concentration ofglucose in the blood at the proper level for use by
organs suchas the brain, whose sole fuel source, under normal
conditions,is glucose.The major energy metabolism pathways include
gly-colysis, glycogen degradation and synthesis,
gluconeogenesis,the pentose phosphate pathway, and triacylglycerol
and fattyacid synthesis, which are cytosolically based, and fatty
acid ox-idation, the citric acid cycle, and oxidative
phosphorylation,which are confined to the mitochondrion. Amino acid
degra-dation occurs, in part, in both compartments. The
mediatedmembrane transport of metabolites therefore also plays an
es-sential metabolic role.
2 Organ Specialization The brain normally consumeslarge amounts
of glucose. Muscle, under intense ATP demandsuch as in sprinting,
degrades glucose and glycogen anaerobi-cally, thereby producing
lactate, which is exported via theblood to the liver for
reconversion to glucose through gluco-neogenesis. During moderate
activity, muscle generates ATPby oxidizing glucose from glycogen,
fatty acids, and ketonebodies completely to CO2 and H2O via the
citric acid cycle andoxidative phosphorylation. Adipose tissue
stores triacylglyc-erols and releases fatty acids into the
bloodstream in responseto the organisms metabolic needs. These
metabolic needs arecommunicated to adipose tissue by means of the
hormones in-sulin, which indicates a fed state in which storage is
appropri-ate, and glucagon, epinephrine, and norepinephrine, which
sig-nal a need for fatty acid release to provide fuel for
othertissues. The liver, the bodys central metabolic
clearinghouse,maintains blood glucose concentrations by storing
glucose asglycogen in times of plenty and releasing glucose in
times ofneed both by glycogen breakdown and by gluconeogenesis.
Italso converts fatty acids to ketone bodies for use by
peripheraltissues. During a fast, it breaks down amino acids
resultingfrom protein degradation to metabolic intermediates that
can
be used to generate glucose. The kidney filters out urea fromthe
blood, recovers important metabolites, and maintains pHbalance. To
do so, glutamine is broken down to produce NH4for H excretion.The
resulting -ketoglutarate product is con-verted to CO2 to resupply
HCO
3 to the blood to maintain
its buffering capacity. During starvation, the kidney uses the
-ketoglutarate from glutamine breakdown for gluconeo-genesis.
3 Metabolic Homeostasis: Regulation of Appetite,Energy
Expenditure, and Body Weight AMP-dependentprotein kinase (AMPK),
the cells fuel gauge, senses the cellsneed for ATP and activates
metabolic breakdown pathwayswhile inhibiting biosynthetic pathways.
Adiponectin, anadipocyte hormone that increases insulin
sensitivity, acts byactivating AMPK. Appetite is suppressed by the
actions ofleptin, a hormone produced by adipose tissue, insulin,
pro-duced by the cells of the pancreas, and PYY336, produced bythe
gastrointestinal tract, which act in the hypothalamus to in-hibit
the secretion of neuropeptide Y (NPY) and stimulate thesecretion of
-MSH and CART. This decreases the appetiteand hence food intake.
Ghrelin, a hormone secreted by theempty stomach, opposes the
actions of leptin, insulin, andPYY336, stimulating appetite and
food intake. Leptin also actsin peripheral tissues to stimulate
energy expenditure by fattyacid oxidation and thermogenesis.
4 Metabolic Adaptation During prolonged starvation,the brain
slowly adapts from the use of glucose as its sole fuelsource to the
use of ketone bodies, thereby shifting the meta-bolic burden from
protein breakdown to fat breakdown. Dia-betes mellitus is a disease
in which insulin either is not se-creted or does not efficiently
stimulate its target tissues,leading to high concentrations of
glucose in the blood andurine. Cells starve in the midst of plenty
since they cannotabsorb blood glucose and their hormonal signals
remain thoseof starvation. Abnormally high production of ketone
bodies isone of the most dangerous effects of uncontrolled
diabetes.Metabolic syndrome is caused by obesity, physical
inactivity,and possibly genetic determinants. It symptoms can be
re-lieved by substances that activate AMPK.
CHAPTER SUMMARY
Chapters 17 to 26 of this text.Batterham, R.L., et al., Gut
hormone PYY336 physiologically in-
hibits food intake, Nature 418, 650654 (2002).Brning, J.C.,
Gautam, D., Burks, D.J., Gillette, J., Schubert, M.,
Orban, P.C., Klein, R., Krone, W., Mller-Weiland, D., andKahn,
C.R., Role of brain insulin receptor in control of bodyweight and
reproduction, Science 289, 21222125 (2000).
Carling, D., The AMP-activated protein kinase cascadea unify-ing
system for energy control, Trends Biochem. Sci. 29, 1824(2004).
Coll,A.P., Farooqi, I.S., and ORahilly, S.,The hormonal control
offood intake, Cell 129, 251262 (2007).
Evans, J.L., Goldfine, I.D., Maddux, B.A., and Grodsky,
G.M.,Oxidative stress and stress-activated signaling pathways:
a
unifying hypothesis of type 2 diabetes, Endocrine Rev. 23,599622
(2002).
Flier, J.S., Obesity wars: Molecular progress confronts an
expand-ing epidemic, Cell 116, 337350 (2004).
Kadowaki, T. and Yamauchi, T., Adiponectin and
adiponectinreceptors, Endocrine Rev. 26, 439451 (2005).
Lowell, B.B. and Spiegelman, B.M., Towards a molecular
under-standing of adaptive thermogenesis, Nature 404, 652660
(2000).
Montague, C.T., et al., Congenital leptin deficiency is
associatedwith severe early-onset obesity in humans, Nature 387,
903908(1997).
Moreno-Aliaga, M.J., Marti, A., Garca-Foncillas, J. and
Martnes,J.A., DNA hybridization arrays: a powerful technology
fornutritional and obesity research, Br. J. Nutr. 86, 119122
(2001).
REFERENCES
JWCL281_c27_1088-1106.qxd 6/8/10 8:49 AM Page 1105
-
1106 Chapter 27. Energy Metabolism: Integration and Organ
Specialization
Nakar, V.A., et al., AMPK and PPAR agonists are
exercisemimetics, Cell 134, 405415 (2008).
Nakazato, M., Murakami, N., Date, Y., Kojima, M., Matsuo,
H.,Kangawa, K., and Matsukara, S., A role for ghrelin in thecentral
regulation of feeding, Nature 409, 194198 (2001).
Schwartz, M.W. and Morton, G.J., Keeping hunger at bay,
Nature418, 595597 (2002).
Shaw, R.J., Lamia, K.A., Vasquez, D., Koo, S.-H., Bardeesy,
N.,DePinho, R.A., Montminy, M., and Cantley, L.C., The kinaseLKB1
mediates glucose homeostasis in