Integration of Metabolism

Question 1

What are the 9 major pathways of metabolism?

What is the only organ that can carry out all these pathways?

Answer 1

1. glycolysis
2. TCA cycle
3. oxidative phosphorylation
4. gluconeogenesis
5. pentose phosphate pathway
6. glycogen metabolism
7. fatty acid metabolism
8. amino acid metabolism
9. nucleotide metabolism

liver

Question 2

What are the 3 key molecules that act as junction points and what their products?

Answer 2

1. glucose-6-phosphate: glucose, glycogen, pyruvate, ribose-5-phosphate
2. pyruvate: acetyl-CoA, lactate, alanine, OAA
3. acetyl CoA: CO2, fatty acids, ketone bodies

Question 3

• MVP of metabolism
• receives blood from enteric circulation (portal vein) and from periphery (hepatic artery)
• processes most incoming nutrients
• responds quickly to dietary conditions
• maintains constant concentrations of nutrients in blood regardless of food intake
• synthesizes and secretes proteins (plasma proteins, antibodies, acute phase proteins)
• processes and detoxifies toxins and waste products

Answer 3

liver

Question 4

What does the liver primarily depend on for its own energy needs?

Answer 4

β-oxidation of fatty acids

Question 5

• synthesizes and stores triacylglycerols (TAGs) as signaled by insulin (fed state)
• uses fatty acids (from chylomicrons and VLDL) to make TAGs
• uses glucose from blood to make TAGs
• degrades TAGs and releases fatty acids and glycerol for other tissues to use as signaled by glucagon/epinephrine (hunger, exercise)

Answer 5

adipose

Question 6

• the energy consumer
• high dependence on blood glucose as fuel source
• uses 20% of total O2 consumed by resting human (accounts for only 2% of body mass)
• some glycogen is stored in astrocytes, breaks down to release glucose for use by neurons
• lactate released from astrocytes as well
• during starvation, switches to metabolism of ketone bodies for energy (metabolized by TCA, prevents protein breakdown for energy, uses AAs for synthetic purposes, makes neurotransmitters and peptide hormones)

Answer 6

brain

Question 7

What is the general function of astrocyte-neuron lactate shuttle?

Answer 7

• pyruvate prod by glycolysis in astrocyte, converted to lactate by LDH5
• shuttled to neuron via MCT 1, 4, and 2
• converted to pyruvate by LDH1
• converted to energy by PDH
• neurons are mainly oxidative, astrocytes are mainly glycolytic

Question 8

• exclusively aerobic as evidenced by the density of mitochondria in the muscle
• complete oxidation of glucose via TCA and ox phos AND β-oxidation of fatty acids serve as major fuel sources
• also uses ketone bodies, consumes acetoacetate in preference to glucose
• also uses AA’s (particularly branched chain AA’s)
• has virtually no glycogen reserves
• lack of O2 leads to tissue death (myocardial infarction)

Answer 8

heart

Question 9

• the consumer of energy
• rich in glycogen (contains 75% of body’s glycogen stores)
• glycogen readily broken down to G-6-P, used by muscle for glycolysis
• lacks glucose 6-phosphatase, so muscle retains glucose, preferred fuel for bursts of activity
• also uses fatty acids and ketone bodies for energy

Answer 9

skeletal muscle

Question 10

What are the 3 systems of ATP generation and their associated temporal utilization?

Answer 10

1. phosphagen (immediate)
2. anaerobic glycolysis (short-term, 2 minutes)
3. aerobic respiration (ox phos, FA mblsm), (long-term)

Question 11

• short bursts of heavy activity (i.e. sprinting)
• quick exhaustion of ATP stores (within 1-2 sec)
• replenished by metabolism of phosphocreatine (within 5-6 sec)
• stored in muscle to quickly regenerate ATP from ADP
• phosphocreatine and ADP are converted to creatine and ATP by phosphocreatine kinase

Answer 11

phosphagen system

Question 12

• further intense activity (past the ATP-PC phase), ~30 sec
• oxidation of free blood glucose or glycogen (glycogenolysis)
• glycogen > G-6P > pyruvate > lactate
• lactate causes decrease in power and muscle fatigue
• must shift to a longer, more sustainable energy prod system

Answer 12

anaerobic glycolysis

Question 13

How does the Cori cycle regenerate glucose from lactate?

Answer 13

• in muscle: glucose converted to pyruvate and lactate via glycolysis
• lactate transported via BS to liver
• lactate converted to pyruvate, which is converted to glucose via gluconeogenesis
• glucose in liver transported back to muscle via BS

Question 14

• metabolic processes that result in reduction of co-enzymes (i.e. formation of NADH and FADH2)
• production of energy from oxidation of NADH and FADH2 (2.5 and 1.5 ATP respectively)
• pumps protons out of the mito matrix, builds up proton conc in the intermembrane space
• produces ATP via ATP synthase

Answer 14

oxidative phosphorylation

Question 15

What are the 5 main organs that are involved in metabolism?

Answer 15

1. liver: processes fats, carbs, proteins from diet; synthesizes/distributes lipids, ketone bodies, and glucose for other tissues; converts excess nitrogen to urea
2. pancreas: secretes insulin and glucagon in response to changes in blood glucose conc
3. adipose tissue: synthesizes, stores, and mobilizes triacylglyceroles
4. skeletal muscle: uses ATP to do mechanical work
5. brain: transports ions to maintain membrane potential; integrates inputs from body and surroundings; sends signals to other organs

Question 16

What is the difference between white and brown adipose tissue?

Answer 16

white fat is accumulated fat from surplus calories (subcutaneous, large effect on hormone regulation) while brown fat has high levels of thermogenin (burn calories and generates heat, the “good” fat)

Question 17

What happens during the fed state within metabolism? (14)

Answer 17

1. in intestine: dietary carbs converted to glucose
2. in intestine: dietary fats converted to TAGs and put in chylomicrons
3. in intestine: dietary proteins converted to AA’s
4. in blood: insulin increases and glucagon decreases
5. in liver: glucose converted to acetyl CoA
6. in liver: glucose stored as glycogen
7. in liver: acetyl CoA converted to TAGs
8. glucose in blood brought to briain
9. glucose in blood brought to RBC’s
10. glucose in blood brought to adipose tissue
11. glucose in blood brought to muscle (converted to ATP fuel and glycogen stores)
12. FA’s and glycerol in blood brought to adipose tissue
13. FA’s, glycerol, and glucose combine in adipose tissue to form TAGs
14. AA’s brought to tissues for protein syn, important compound synthesis, and ATP fuel prod

Question 18

What happens in the liver during fed state?

Answer 18

• glycolysis (don’t need glucose, need energy)
• glycogen synthesis
• TAG synthesis

Question 19

What happens during the fasting state within metabolism? (12)

Answer 19

1. blood glucose and insulin decrease, glucagon increases
2. in liver: glycogen is broken down into glucose
3. glucose from liver is brought to brain
4. glucose from liver is brought to RBC’s
5. in adipose tissue: TAGs are broken down into FA’s and glycerol
6. FA’s from adipose tissue is brought to muscle where they are converted to acetyl CoA and ATP
7. in liver: acetyl CoA is converted to ketone bodies
8. ketone bodies fom liver are brought to muscle for energy prod
9. in muscles: protein is broken down into AA’s and brought to liver to be converted to glucose
10. urea from liver is transported to kidneys and excreted
11. lactate from RBC’s is brought to liver and converted to glucose
12. glycerol from broken down TAG’s in adipose is brought to liver and converted to glucose

Question 20

What happens in the liver during fasting state?

Answer 20

• glycogenolysis
• gluconeogenesis
• fatty acid oxidation
• ketone body formation

Question 21

Whats happens during starvation state within metabolism?

Answer 21

Similar to fasting state, except glycogen stores are depleted, thus glycogenolysis is halted and ketone bodies are shuttled to the brain instead of muscles

Question 22

Insulin (high blood glucose)

Metabolic effect:

• increased glucose uptake (muscle, adipose) increases _____ transporter (____)
• increased glucose uptake (liver) increases ________ enzyme expression
• increased glycogen synthesis (liver, muscle) increases _______ _______
• decreased glycogen breakdown (liver, muscle) decreases _______ _________
• increased glycolysis, acetyl CoA prod (liver, muscle) increases _____ (by increase in PFK-2) and increases _______ __________ complex
• increased fatty acid syn (liver) increases ______ _____ _________
• increased triacylglycerol (adipose tissue) increases _______ ______ (capillary)

Answer 22

• glucose, GLUT4
• glucokinase
• glycogen synthase
• glycogen phosphorylase
• PFK-1, pyruvate dehydrogenase
• acetyl CoA carboxylase
• lipoprotein lipase

Question 23

Glucagon (low blood glucose)

• increased glycogen break down (liver) increases ______ _________
• decreased glycogen synthesis (liver) decreases ______ _______
• decreased glycolysis (liver) decreases _____
• increased gluconeogenesis (liver) increases ______, decreases ______ ______, and increases ____ _________
• increased fatty acid metabolism (adipose tissue) increases __________ _____ and ______ _________
• increased ketogenesis decreases _____ _____ _______

Answer 23

• glycogen phosphorylase
• glycogen synthase
• PFK-1
• FBPase-2, pyruvate kinase, PEP carboxylase
• triacyglycerol lipase, perilipin phosphorylation
• acetyl CoA carboxylase

Question 24

Epinephrine (fight or flight)

• increased heart rate, blood pressure, and dilation of respiratory passages increases ______ of ___ to tissues (muscle)
• increased glycogen breakdown (muscle, liver), increased gluconeogenesis (liver), and decreased glycogen synthesis (muscle, liver) increases production of _______ for fuel
• increased glycolysis (muscle) increases ____ production in muscle
• increased FA mobilization (adipose) increases availability of _____ ____ as fuel
• increased glucagon secretion and decreased insulin secretion reinforces ________ _____ of epi

Answer 24

• delivery O2
• glucose
• ATP
• fatty acids
• metabolic effects

Question 25

What are the satiation signals in the body?

Answer 25

• cholecystokinin (CCK) and glucagon-like peptide 1 (GLP-1) secreted by small intestine in response to a meal
• induce feelings of satiety in brain
• induce increased insulin secretion and increased insulin biosyn in pancreas (especially GLP-1)

Question 26

How does CCK signal from GI tract function specifically in inducing satiety?

Answer 26

• short term signal that relays satiety from gut to various regions of brain
• peptide hormone that is secreted into blood by cells in duodenum and jejunum regions as postprandial satiation signal
• binds to its receptor, GPCR, located in various peripheral neurons that relay signals to brain
• binding initiates signal-transduction pathway in brain that generates feeling of satiety
• CCK also helps in digestion, by stimulating secretion of pancreatic enzymes and bile salts from gallbladder

Question 27

How does GLP-1 signal from GI tract function specifically in inducing satiety?

Answer 27

• secreted by intestinal L cells (hormone secreting cells)
• has variety of effects, mediated via binding to its GPCR receptor
• induces feelings of satiety that inhibit further eating
• also potentiates glucose-induced insulin secretion by β cells of pancreas while inhibiting glucagon secretion

Question 28

What is the role of ghrelin in appetite signaling?

Answer 28

• peptide secreted by stomach, acts on regions of the hypothalamus to stimulate appetite through its GPCR receptor
• secretion increases before a meal and decreases afterward

Question 29

What 2 key signal molecules regulate energy homeostasis over the time scale of hours or days?

Answer 29

• leptin: hormone secreted by adipocytes, reports on status of TAG stores
• insulin: secreted by β cells of pancreas, reports on status of blood glucose/carb availability

Question 30

• an adipokine that is secreted by adipose tissue in direct proportion to fat mass
• more fat = more ____
• ____ receptors are all over the body
• receptor signaling: increases sensitivity of muscle/liver to insulin, stimulate β oxidation of FAs, decrease TAG synthesis

Answer 30

leptin

Question 31

What is the important role of leptin signaling to the brain?

Answer 31

• regulates body weight
• inhibits food intake
• stimulates energy expenditure

(leptin knockout mice are obese, display hyperphagia, hyperlipidemia, and insensitivity to insulin)

Question 32

• contributes to obesity
• role of a group of proteins called suppressors of cytokine signaling (SOCS)
• inhibit receptor action by: binding to receptor, binding to other signaling pathway components, enhancing proteolytic degradation of receptor
• SOCS knockout mouse: displays enhanced sensitivity to leptin, resistant to weight even on high fat diet

Answer 32

leptin and insulin resistance

Question 33

• energy sensor in cell
• inactivated by ATP, activated by AMP
• low cell ATP levels: ____ phosphorylates specific enzymes and growth control nodes to increase ATP prod (catabolism) and decrease ATP consumption (anabolism)
• exists universally as complexes of 3 different protein subunits (heterotrimers) comprising a catalytic α subunit that carries the protein kinase activity, and regulatory β and γ subunits
• competition between ATP and AMP for binding to ____ allosteric sites determines its activity

Answer 33

AMP-activated protein kinase (AMPK)