chapter 27 metabolic integration and organ specialization biochemistry by reginald garrett and...
Post on 19-Dec-2015
230 views
TRANSCRIPT
![Page 1: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/1.jpg)
Chapter 27
Metabolic Integration and Organ Specialization
Biochemistry
by
Reginald Garrett and Charles Grisham
![Page 2: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/2.jpg)
Outline1. Can systems analysis simplify the complexity of
metabolism?2. What underlying principle relates ATP coupling
to the thermodynamics of metabolism?3. Is there a good index of cellular energy status?4. How is overall energy balance regulated in
cells?5. How is metabolism integrated in a multicellular
organism?6. What regulates our eating behavior?7. Can you really live longer by eating less?
![Page 3: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/3.jpg)
27.1 – Can Systems Analysis Simplify the Complexity of Metabolism?
• The metabolism can be portrayed by a schematic diagram consisting of just three interconnected functional block:
1. Catabolism
2. Anabolism
3. Macromolecular synthesis and growth
• Catabolic and anabolic pathways, occurring simultaneously, must act as a regulated, orderly, responsive whole
![Page 4: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/4.jpg)
Figure 27.1 Block diagram of intermediary metabolism.
![Page 5: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/5.jpg)
• Catabolism:– Foods are oxidized to CO2 and H2O
– The formation of ATP– Reduce NADP+ to NADPH– The intermediates serve as substrates for
anabolism
Glycolysis
The citric acid cycle
Electron transport and oxidative phosphorylation
Pentose phosphate pathway
Fatty acid oxidation
![Page 6: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/6.jpg)
• Anabolism:– The biosynthetic reactions – The chemistry of anabolism is more complex– Metabolic intermediates in catabolism are the
precursor for anabolism– NADPH supplies reducing power– ATP is the coupling energy
• Macromolecular synthesis and growth– Creating macromolecules– Macromolecules are the agents of biological
function and information– Growth can be represented as cellular
accumulation of macromolecules
![Page 7: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/7.jpg)
• Only a few intermediates interconnect the major metabolic systems– Sugar-phosphates (triose-P, tetraose-P, pentose-P,
and hexose-P) -keto acids (pyruvate, oxaloacetate, and -
ketoglutarate) – CoA derivs (acetyl-CoA and suucinyl-CoA)– PEP
• ATP & NADPH couple catabolism & anabolism
• Phototrophs also have photosynthesis and CO2 fixation systems
![Page 8: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/8.jpg)
27.2 – What Underlying Principle Relates ATP Coupling to the Thermodynamics of
Metabolism?Three types of stoichiometry in biological systems 1. Reaction stoichiometry - the number of each
kind of atom in a reaction 2. Obligate coupling stoichiometry - the required
coupling of electron carriers 3. Evolved coupling stoichiometry - the number
of ATP molecules that pathways have evolved to consume or produce - a number that is a compromise
![Page 9: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/9.jpg)
The number of each kind of atom in any chemical reaction remains the same, and thus equal numbers must be present on both sides of the equation
C6H12O6 + 6 O2 6 CO2 + 6 H2O
1. Reaction stoichiometry
![Page 10: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/10.jpg)
Cellular respiration is an oxidation-reduction process, and the oxidation of glucose is coupled to the reduction of NAD+ and FAD
(a) C6H12O6 + 10 NAD+ + 2 FAD + 6 H2O 6 CO2 + 10 NADH + 10 H+ + 2 FADH2
(b) 10 NADH + 10 H+ + 2 FADH2 + 6 O2 12 H2O + 10 NAD+ + 2 FAD
2. Obligate coupling stoichiometry
![Page 11: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/11.jpg)
• The coupled formation of ATP by oxidative phosphorylation
C6H12O6 + 6 O2 + 38 ADP + 38 Pi 6 CO2 + 38 ATP + 44 H2O
• Prokaryotes: 38 ATP
• Eukaryotes: 32 or 30 ATP
3. Evolved coupling stoichiometry
![Page 12: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/12.jpg)
ATP coupling stoichiometry determines the Keq for metabolic sequence
• The energy release accompanying ATP hydrolysis is transmitted to the unfavorable reaction so that the overall free energy for the coupled process is negative (favorable)– The involvement of ATP alters the free energy change
for a reaction– the role of ATP is to change the equilibrium ratio of
[reactants] to [products] for a reaction
• The cell maintains a very high [ATP]/([ADP][Pi]) ratio
![Page 13: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/13.jpg)
• The cell maintains a very high [ATP]/([ADP][Pi]) ratio – ATP hydrolysis can serve as the driving force for
virtually all biochemical events– Living cells break down energy-yielding nutrient
molecules to generate ATP
![Page 14: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/14.jpg)
1. ATP is the energy currency of the cells– To establish large equilibrium constant for
metabolic conversions– To render metabolic sequence
thermodynamically favorable
2. An important allosteric effector in the kinetic regulation of metabolism
• PFK in glycolysis• FBPase in gluconeogenesis
ATP has two metabolic roles
![Page 15: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/15.jpg)
27.3 – Is there a good index of cellular energy status??
• Energy transduction and energy storage in the adenylate system – ATP, ADP, and AMP – lie at the very heart of metabolism – The regulation of metabolism by adenylates in turn
requires close control of the relative concentrations of ATP, ADP, and AMP
– ATP, ADP, and AMP are all important effectors in exerting kinetic control on regulated enzymes
![Page 16: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/16.jpg)
• Adenylate kinase interconverts ATP, ADP, and AMP
ATP + AMP 2 ADP
• Adenylate kinase provides a direct connection among all three members of the adenylate pool
• Adenylate pool: [ATP] + [ADP] + [AMP]
• Adenylates provide phosphoryl groups to drive thermodynamically unfavorable reactions
![Page 17: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/17.jpg)
• Energy charge is an index of how fully charged adenylates are with phosphoric anhydrides
Energy charge =
• If [ATP] is high, E.C.1.0
• If [ATP] is low, E.C. 0
[ATP] + ½ [ADP]
[ATP] + [ADP] + [AMP]
Energy Charge Relates the ATP Levels to the Total Adenine Nucleotide Pool
![Page 18: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/18.jpg)
Figure 27.2Relative concentrations of AMP, ADP, and ATP as a function of energy charge. (This graph was constructed assuming that the adenylate kinase reaction is at equilibrium and that G°' for the reaction is -473 J/mol; Keq = 1.2.)
![Page 19: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/19.jpg)
• Regulatory enzymes typically respond in reciprocal fashing to adenine nucleotides– For example, phosphofructokinase is stimulated
by AMP and inhibited by ATP
• Regulatory enzymes in energy-producing catabolic pathways show greater activity at low energy charge– PFK and pyruvate kinase
• Regulatory enzymes of anabolic pathways are not very active at low energy charge– Acetyl-CoA carboxylase
Key enzymes are regulated by Energy charge
![Page 20: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/20.jpg)
0.85 - 0.88
Figure 27.3 Responses of regulatory enzymes to variation in energy charge.
![Page 21: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/21.jpg)
27.4 – How is Overall Energy Balance Regulated in Cells?
• AMP-activated protein kinase (AMPK) is the cellular energy sensor– Metabolic inputs to this sensor determine whether its
output (protein kinase activity) takes place– When ATP is high, AMPK is inactive– When ATP is low, AMPK is allosterically activated
and phosphorylates many targets controlling cellular energy production and consumption
– The competition between ATP and AMP for binding to the AMPK allosteric sites determines the activity of AMPK
![Page 22: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/22.jpg)
Figure 27.4 Domain structure of the AMP-activated protein kinase (AMPK) subunits.
• AMPK is an heterotrimer; the -subunit is the catalytic subunit and the -subunit is regulatory
• The -subunit has an -binding domain that brings and together
![Page 23: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/23.jpg)
• AMPK targets key enzymes in energy production and consumption– Activation of AMPK leads to phosphorylation of
many key enzymes in energy metabolism– Include phosphorylation of PFK-2 (in liver);
glycogen synthase; ACC; HMG-CoA reductase– Phosphorylation of transcription factors diminishes
expression of gene encoding biosynthetic enzymes
• AMPK controls whole-body energy homeostasis
![Page 24: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/24.jpg)
Figure 27.6 AMPK regulation of energy production and consumption in mammals.
![Page 25: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/25.jpg)
27.5 – How Is Metabolism Integrated in a Multicellular Organism?
• Organ systems in complex multicellular organisms have arisen to carry out specific physiological functions
• Such specialization depends on coordination of metabolic responsibilities among organs so that the organism as a whole can thrive
• Organs differ in the metabolic fuels they prefer as substrates for energy production (see Figure 27.7)
![Page 26: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/26.jpg)
Figure 27.7 Metabolic relationships among the major human organs.
![Page 27: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/27.jpg)
27.5 – How Is Metabolism Integrated in a Multicellular Organism?
• The major fuel depots in animals are glycogen in live and muscle; triacylglycerols in adipose tissue; and protein, mostly in skeletal muscle
• The usual order of preference for use of these is glycogen > triacylglycerol > protein
• The tissues of the body work together to maintain energy homeostasis
![Page 28: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/28.jpg)
![Page 29: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/29.jpg)
BrainBrain has two remarkable metabolic features
1. very high respiratory metabolism20 % of oxygen consumed is used by the brain
2. but no fuel reservesUses only glucose as a fuel and is dependent on the blood for
a continuous incoming supply (120g per day)
In fasting conditions, brain can use -hydroxybutyrate (from fatty acids in liver), converting it to acetyl-CoA for the energy production via TCA cycle
Generate ATP to maintain the membrane potentials essential for transmission of nerve impulses
![Page 30: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/30.jpg)
Figure 27.8 Ketone bodies such as β-hydroxybutyrate provide the brain with a source of acetyl-CoA when glucose is unavailable.
![Page 31: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/31.jpg)
Muscle• Skeletal muscles is responsible for about 30%
of the O2 consumed by the human body at rest• Muscle contraction occurs when a motor never
impulse causes Ca+2 release from endomembrane compartments
• Muscle can utilize a variety of fuels --glucose, fatty acids, and ketone bodies
• Rest muscle contains about 2% glycogen and 0.08% phoshpocreatine
![Page 32: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/32.jpg)
Creatine Kinase in Muscle• About 4 seconds of exertion, phosphocreatine
provide enough ATP for contraction• During strenuous exertion, once
phosphocreatine is depleted, muscle relies solely on its glycogen reserves
• Glycolysis is capable of explosive bursts of activity, and the flux of glucose-6-P through glycolysis can increase 2000-fold almost instantaneously
• Glycolysis rapidly lowers pH (lactate accumulation), causing muscle fatigue
![Page 33: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/33.jpg)
Creatine Kinase and Phosphocreatine Provide an Energy Reserve in Muscle
Figure 27.9 Phosphocreatine serves as a reservoir of ATP-synthesizing potential.
![Page 34: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/34.jpg)
Muscle Protein Degradation
• During fasting or excessive activity, amino acids are degraded to pyruvate, which can be transaminated to alanine
• Alanine circulates to liver, where it is converted back to pyruvate – a substrate for gluconeogenesis
• This is a fuel of last resort for the fasting or exhausted organism
![Page 35: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/35.jpg)
Figure 27.10 The transamination of pyruvate to alanine by glutamate:alanine aminotransferase.
![Page 36: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/36.jpg)
Heart
• The activity of heart muscle is constant and rhythmic
• The heart functions as a completely aerobic organ and is very rich in mitochondria
• Prefers fatty acid as fuel
• Continually nourished with oxygen and free fatty acid, glucose, or ketone bodies as fuel
![Page 37: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/37.jpg)
Adipose tissue• Amorphous tissue widely distributed about
the body• Consist of adipocytes• ~65% of the weight of adipose tissue is
triacylglycerol• continuous synthesis and breakdown of
triacylglycerols, with breakdown controlled largely via the activation of hormone-sensitive lipase
• Lack glycerol kinase; cannot recycle the glycerol of TAG
![Page 38: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/38.jpg)
Brown fat• A specialized type of adipose tissue, is
found in newborn and hibernating animals
• Rich in mitochondria
• Thermogenin, uncoupling protein-1, permitting the H+ ions to reenter the mitochondria matrix without generating ATP
• Is specialized to oxidize fatty acids for heat production rather than ATP synthesis
![Page 39: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/39.jpg)
Liver
• The major metabolic processing center in vertebrates, except for triacylglycerol
• Most of the incoming nutrients that pass through the intestines are routed via the portal vein to the liver for processing and distribution
• Liver activity centers around glucose-6-phosphate
![Page 40: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/40.jpg)
• Glucose-6-phosphate– From dietary carbohydrate, degradation of
glycogen, or muscle lactate– Converted to glycogen– released as blood glucose, – used to generate NADPH and pentoses via the
pentose phosphate pathway, – catabolized to acetyl-CoA for fatty acid synthesis
or for energy production in oxidative phosphorylation
• Fatty acid turnover• Cholesterol synthesis• Detoxification organ
![Page 41: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/41.jpg)
Figure 27.11Metabolic conversions of glucose-6-phosphate in the liver.
![Page 42: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/42.jpg)
27.6 What Regulates Our Eating Behavior?
• Approximately two-thirds of American are overweight
• One-third of Americans are clinically obese
• Obesity is the most important cause of type 2 diabetes
• Research into the regulatory controls on feeding behavior has become a medical urgency
• The hormones that control eating behavior come from many different tissues
![Page 43: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/43.jpg)
Are you hungry • The hormones control eating behavior
– Produced in the stomach, liver,….– Move to brain and act on neurons within the
arcuate nucleus region of the hypothalamus
• The hormones are divided into 1. Short-term regulator: determine individual meal2. Long-term regulator: act as stabilize the levels of
body fat deposit
• Two subset neurons1. NPY/ AgRP producing neurons -- stimulating2. Melanocortin producing neurons-- inhibiting
![Page 44: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/44.jpg)
Figure 27.12 The regulatory pathways that control eating.
![Page 45: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/45.jpg)
• AgRP (agouti-related peptide)– Block the activity of melanocortin-producing
neurons
• Melanocortin– Inhibit the neurons initiating eating behavior– Including - and -MSH (melanocyte-stimulating
hormone)
• Ghrelin and cholecytokinin are short-term regulators of eating behavior
– Ghrelin is an appetite-stimulating peptide hormone produced in the stomach
– Cholecytokinin signal satiety and tends to curtail further eating
![Page 46: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/46.jpg)
• Insulin and leptin are long-term regulators of eating behavior
– Insulin is produced in the -cells of the pancreas when blood glucose level raiseinsulin
– Insulin stimulates fat cells to make leptin• Leptin is an anorexic (appetite-suppressing) agent
• NPY is a orexic (appetite-stimulating) hormone
– PYY3-36 inhibits eating by acting on the NPY/AgRP-producing neurons
![Page 47: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/47.jpg)
• AMPK mediates many of the hypothalamic responses to these hormones
– The actions of leptin, gherlin, and NPY converge at AMPK
– Leptin inhibits AMPK– Gherlin and NPY activate hypothalamic AMPK
• The effects of AMPK may be mediated through changes in malonyl-CoA levels
• AMPK phosphorylates ( inhibits) acetyl-CoA carboxylase
• malonyl-CoA levels decreased
• Low [malonyl-CoA] is associated with increased food intake
![Page 48: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/48.jpg)
27.7 Can You Really Live Longer by Eating Less?
Caloric restriction leads to longevity• For most organisms, caloric restriction results in
– lower blood glucose levels– declines in glycogen and fat stores– enhanced responsiveness to insulin– lower body temperature– diminished reproductive capacity
• Caloric restriction also diminishes the likelihood for development of many age-related diseases, including cancer, diabetes, and atherosclerosis
![Page 49: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/49.jpg)
Mutations in the SIR2 Gene Decrease Life Span
• Deletion of a gene termed SIR2 (silent information regulator 2) abolishes the ability of caloric restriction to lengthen life in yeast and roundworms– This implicates the SIR2 gene product in longevity
• The human gene analogous to SIR2 is SIRT1, for sirtuin 1• Sirtuins are NAD+-dependent protein deacetylases
– The tissue NAD+/NADH ratio controls sirtuin protein deacetylase activity
– Nicotinamide and NADH are inhibitors of the deacetylase reaction
– Oxidative metabolism, which drives conversion of NADH to NAD+, enhances sirtuin activity
![Page 50: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/50.jpg)
Figure 27.13 The NAD+-dependent protein deacetylase reaction of sirtuins.
![Page 51: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/51.jpg)
SIRT1 is a Key Regulator in Caloric Restriction• SIRT1 connects nutrient availability to the expression of
metabolic genes– A striking feature of CR is the loss of fat stores and reduction
of WAT (white adipose tissue)
– SIRT1 participates in the transcriptional regulation of adipogenesis through interaction with PPAR (peroxisome proliferator-activator receptor- )
– PPAR is a nuclear hormone receptor that activates transcription of genes involved in adipogenesis and fat storage
• SIRT1 binding to PPAR represses transcription of these genes, leading to loss of fat stores.
• Because adipose tissue functions as an endocrine organ, this loss of fat has significant hormonal consequences for energy metabolism
![Page 52: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/52.jpg)
SIRT1 is a Key Regulator in Caloric Restriction• SIRT1 connects nutrient availability to the expression of
metabolic genes• SIRT1 participates in the transcriptional regulation of
adipogenesis through interaction with PPAR (peroxisome proliferator-activator receptor- )
• PPAR is a nuclear hormone receptor that activates transcription of genes involved in adipogenesis and fat storage
• SIRT1 binding to PPAR represses transcription of these genes, leading to loss of fat stores.
• Because adipose tissue functions as an endocrine organ, this loss of fat has significant hormonal consequences for energy metabolism
![Page 53: Chapter 27 Metabolic Integration and Organ Specialization Biochemistry by Reginald Garrett and Charles Grisham](https://reader035.vdocument.in/reader035/viewer/2022062221/56649d385503460f94a11d22/html5/thumbnails/53.jpg)
Resveratrol in Red Wine is a Potent Activator of Sirtuin Activity
Figure 27.14 Resveratrol, a phytoalexin, is a member of the polyphenol class of natural products. It is a free-radical scavenger, which may explain its cancer preventive properties.
French people enjoy longevity despite a high-fat diet. Resveratrol may be the basis of this “French paradox”.