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Integration of Metabolism

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Integration of Metabolism Interconnection of pathways Metabolic profile of organs Food intake, starvation and obesity Fuel choice during exercise – PowerPoint PPT presentation

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Title: Integration of Metabolism


1
Integration of Metabolism
  • Interconnection of pathways
  • Metabolic profile of organs
  • Food intake, starvation and obesity
  • Fuel choice during exercise
  • Ethanol alters energy metabolism
  • Hormonal regulation of metabolism

2
Connection of Pathways
  • ATP is the universal currency of energy
  • ATP is generated by oxidation of glucose, fatty
    acids, and amino acids common intermediate -gt
    acetyl CoA electron carrier -gt NADH and FADH2
  • NADPH is major electron donor in reductive
    biosynthesis
  • Biomolecules are constructed from a small set of
    building blocks
  • Synthesis and degradation pathways almost always
    separated -gt Compartmentation !!!

3
Key Junctions between Pathways
4
Metabolic Profile of Organs
5
1. Metabolic Profile of Brain
Glucose is fuel for human brain -gt consumes
120g/day -gt 60-70 of utilization of glucose in
starvation -gt ketone bodies can replace glucose
6
2. Metabolic Profile of Muscles
Major fuels are glucose, fatty acids, and ketone
bodies -gt has a large storage of glycogen -gt
about ¾ of all glycogen stored in muscles -gt
glucose is preferred fuel for burst of activity
-gt production of lactate (anaerobe) -gt fatty acid
major fuel in resting muscles and in heart muscle
(aerobe)
7
3. Metabolic Profile of Adiposite tissue
Triacylglycerols are stored in tissue -gt enormous
reservoir of metabolic fuel -gt needs glucose to
synthesis TAG -gt glucose level determines if
fatty acids are released into blood
8
4. Metabolic Profile of Kidney
Production of urine -gt secretion of waste
products Blood plasma is filtered (60 X per day)
-gt water and glucose reabsorbed -gt during
starvation -gt important site of gluconeogenesis
(1/2 of blood glucose)
9
5. Metabolic Profile of the Liver (Glucose)
Essential for providing fuel to brain, muscle,
other organs -gt most compounds absorpt by diet
-gt pass through liver -gt regulates metabolites
in blood
10
Metabolic Activities of the Liver (Amino Acids)
a-Ketoacids (derived from amino acid degradation)
-gt livers own fuel
11
Metabolic Activities of the Liver (Fatty Acids)
cannot use acetoacetate as fuel -gt almost no
transferase to generate acetyl-CoA
12
Food Intake, Starvation, and Obesity
  • Normal Starved-Fed Cycle
  • Postabsorptive state -gt after a meal
  • Early fasting state -gt during the night
  • Refed state -gt after breakfast
  • -gt Major goal is to maintain blood-glucose level!

13
Blood-Glucose
14
  • Postabsorptive state

Glucose Amino acids -gt transport from intestine
to blood Dietary lipids transported -gt lymphatic
system -gt blood Glucose stimulates -gt secretion
of insulin Insulin -gt signals fed state -gt
stimulates storage of fuels and synthesis of
proteins -gt high level -gt glucose enters muscle
adipose tissue (synthesis of TAG) -gt stimulates
glycogen synthesis in muscle liver -gt
suppresses gluconeogenesis by the liver -gt
accelerates glycolysis in liver -gt increases
synthesis of fatty acids -gt accelerates uptake of
blood glucose into liver -gt glucose 6-phosphate
more rapidly formed than level of blood glucose
rises -gt built up of glycogen stores
15
Insulin Secretion Stimulated by Glucose Uptake
16
Postabsorptive State -gt after a Meal
17
2. Early Fasting State
Blood-glucose level drops after several hours
after the meal -gt decrease in insulin secretion
-gt rise in glucagon secretion Low blood-glucose
level -gt stimulates glucagon secretion of a-cells
of the pancreas Glucagon -gt signals starved
state -gt mobilizes glycogen stores (break
down) -gt inhibits glycogen synthesis -gt main
target organ is liver -gt inhibits fatty acid
synthesis -gt stimulates gluconeogenesis in
liver -gt large amount of glucose in liver
released to blood stream -gt maintain
blood-glucose level Muscle Liver use fatty
acids as fuel when blood-glucose level drops
18
Early Fasting State -gt During the Night
19
3. Refed State
Fat is processed in same way as normal fed
state First -gt Liver does not absorb glucose
from blood (diet) Liver still synthesizes glucose
to refill livers glycogen stores When liver has
refilled glycogen stores blood-glucose level
still rises -gt liver synthesizes fatty acids from
excess glucose
20
Prolonged Starvation
Well-fed 70 kg human -gt fuel reserves about
161,000 kcal -gt energy needed for a
24 h period -gt 1600 kcal - 6000 kcal
-gt sufficient reserves for
starvation up to 1 3 months
-gt however glucose reserves are
exhausted in 1 day Even under starvation -gt
blood-glucose level must be above 40 mg/100 ml
21
Prolonged Starvation
First priority -gt provide sufficient glucose to
brain and other tissues that are dependent on
it Second priority -gt preserve protein -gt shift
from utilization of glucose to utilization of
fatty acids ketone bodies -gt mobilization of
TAG in adipose tissues gluconeogenesis by liver
-gt muscle shift from glucose to fatty acids as
fuel After 3 days of starvation -gt liver forms
large amounts of ketone bodies (shortage of
oxaloacetate) -gt released into blood -gt brain and
heart start to use ketone bodies as fuel After
several weeks of starvation -gt ketone bodies
major fuel of brain After depletion of TAG stores
-gt proteins degradation accelerates -gt death due
to loss of heart, liver, and kidney function
22
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23
Mobilization at Starvation
Also at not treated diabetes
24
Diabetes Mellitus Insulin Insufficiency
  • Characterized by -gt high blood-glucose level
  • -gt Glucose overproduced by liver
  • -gt glucose underutilized by other organs
  • -gt shift in fuel usage from carbohydrates to fats
    -gt keton bodies (shortage of oxaloacetate)
  • -gt high level of keton bodies -gt kidney cannot
    balance pH any more -gt lowered pH in blood and
    dehydration -gt coma
  • Type I diabetes insulin-dependent diabetes
    (requires insulin to live)
  • caused by autoimmune
    destruction of ß-cells
  • begins before age 20
  • -gt insulin absent -gt
    glycagon present
  • -gt person in
    biochemical starvation mode high blood-glucose
    level
  • -gt entry of glucose
    into cells is blocked
  • -gt glucose excreted
    into urine -gt also water excreted -gt feel hungry
    thirsty
  • Type II diabetes insulin-independent diabetes
  • have a normal-high
    level of insulin in blood -gt unresponsive to
    hormone
  • develops in
    middle-aged, obese people

25
Obesity
Mouse lacking leptin or Leptin receptor
In the U. S. -gt about 70 of adults are suffering
from obesity (2009) Risk factor for Diabetes
Cardiovascular diseases Cause of Obesity -gt more
food consumed than needed -gt storage of energy as
fat Two important signals for caloric
homeostasis and appetite control -gt insulin
leptin
26
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27
The Role of Leptin and Insulin on Weight Control
Leptin is a hormone that is produced in direct
proportion to fat mass (adipocytes)
28
High Levels of Leptin and Insulin are a Signal
for caloric homeostasis
29
Obese People Produce More Heat
  • Body can deal with excess calories
  • Storage
  • Extra exercise
  • Production of heat

30
Fuel Choice During Exercise
Fuels used are different in -gt sprinting -gt
anaerobic exercise -gt lactate -gt distance running
-gt aerobic exercise -gt CO2 ATP directly powers
myosin -gt responsible for muscle contraction -gt
movement -gt amount of ATP in muscle is small -gt
velocity depended on rate of ATP production -gt
creatine phosphate generates ATP under intense
muscle contractions for 5-6 s Sprint powered by
ATP, creatine phosphate, and anaerobic glycolysis
of glycogen -gt lactate Medium length sprint
complete oxidation of muscle glycogen -gt CO2
(production slower) -gt velocity lower Marathon
complete oxidation of muscle and liver glycogen
-gt CO2 and complete oxidation
of fatty acids from adipose tissues -gt CO2 (ATP
is generated even slower) Low
blood-glucose level -gt high glucagon/insulin
ratio -gt mobilization of fatty acids
31
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32
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33
Ethanol Alters Energy Metabolism in Liver
  • Consumption of EtOH in excess -gt number of health
    problems
  • EtOH has to be metabolised
  • EtOH NAD -gt Acetaldehyde NADH
    (alcohol dehydrogenase, in cytoplasm)
  • Acetaldehyde NAD -gt Acetate NADH
    (aldehyde dehydrogenase, in mitochondria)
  • -gt EtOH consumption leads to accumulation of NADH
  • High level NADH causes
  • -gt inhibition of gluconeogenesis (prevent
    oxidation of lactate to pyruvate) -gt lactate
    accumulates
  • -gt inhibits fatty acid oxidation -gt stimulates
    fatty acid synthesis in liver -gt TAG accumulates
    -gt fatty liver
  • -gt inhibition of citric acid cycle
  • Ethanol inducible microsomal ethanol-oxidizing
    system (MEOS) -gt P450 dependent pathway -gt
    generates free oxygen radicals -gt damages tissues
  • Acetate is converted into Acetyl CoA -gt
    processing of Acetyl CoA by citric acid cycle is
    blocked by high amounts of NADH -gt Ketone bodies
    are generated and released into the blood -gt
    further drop of pH
  • Processing of acetate in liver inefficient -gt
    high level of acetaldehyde in liver -gt reacts
    with proteins -gt become inactive -gt damage liver
    -gt cell death
  • Liver damage in 3 stages Development of Fatty
    Liver -gt alcoholic hepatitis (groups of cells
    die) -gt cirrhosis (no convertion of Ammonium -gt
    urea)

34
Hormonal Regulation of Metabolism
35
Action of Different Hormones
36
Hormone signals and their target tissues
37
Cascade of Hormone Release Following Central
Nervous System Input to the Hypothalamus
  • Cortisol
  • Signals stress !!!
  • signals low blood glucose -gt counterbalances
    insulin

38
Epinephrine -gt Signals Stress -gt requires
activity -gt Fighting or Fleeing
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