L2 - Overview of metabolic regulation and integration

Question 1

Core concepts in metabolic integration

Answer 1

1 - Multiple regulatory mechanisms can target a single protein
2 - Single pathway can be regulated at multiple steps (often by different mechanisms)
3 - Control of one protein can have secondary actions

Question 2

Regulation of opposing pathways: how is it managed without wastefully synthesising and degrading substances and what enzymes must be present for this process?

Answer 2

Reciprocal regulation of opposing pathways occurs - when one pathway is increased the other is reduced

Would not be possible if both pathways were catalysed by the same enzymes - at least one step is catalysed by different enzymes in the catabolic and anabolic directions – regulated separately

Opposing catabolic and anabolic pathways may also occur in different subcellular compartments

Question 3

Pancreas: what is it, what part of it secretes hormones, and what is the pathway of secreted hormones?

Answer 3

Organ that secretes hormones in response to blood glucose levels

Islets of Langerhans (α/β cells)

Hormones released into the hepatic portal vein – first transported to liver and adipose tissue

Question 4

Brain

Answer 4

Integrates inputs from surroundings and sends signals to other parts of the body

Question 5

Liver

Answer 5

• Processes fats, carbohydrates, and proteins from the diet
• Synthesises and distributes lipids, ketones, and glucose
• Converts excess nitrogen into urea

Question 6

Lymphatic system

Answer 6

Carries lipids from intestines to liver

Question 7

Adipose tissue

Answer 7

• Synthesises, stores, and mobilises triacylglycerols
• Brown adipose tissue carries out thermogenesis

Question 8

Skeletal muscle

Answer 8

Uses ATP to contract muscles, resulting in movement

Question 9

Cardiac muscle

Answer 9

Uses ATP to pump blood around the body

Question 10

Portal vein

Answer 10

Carries nutrients from intestine to liver

Question 11

Small intestine

Answer 11

Absorbs nutrients from the diet and transports them into either circulatory or lymphatic system

Question 12

Hormonal regulation of metabolism

Answer 12

Hormones are carried by the bloodstream to nearby cells or more distant tissues/organs - bringing about metabolic changes in target cells

Question 13

Insulin: what is it, when is it released, and what does it do?

Answer 13

Peptide hormone

Released by pancreatic β-cells in response to high blood glucose levels

• Stimulates glucose transport into cells
• Stimulates synthesis of fat, glycogen and protein
• Inhibits the breakdown of fat, glycogen and protein
• Essentially causes a coordinated change in metabolism

Question 14

Glucagon: what is it, when is it released, what does it target, and what does it do?

Answer 14

Peptide hormone

Released by pancreatic α-cells in response to low blood glucose

Liver, primarily

• Inhibits synthesis of fat, glycogen and protein
• Stimulates breakdown of fat, glycogen and protein
• Promotes mobilisation of fuel storage

Question 15

Epinephrine: what is it, when is it released, what does it target, and what does it do?

Answer 15

Tyrosine-derived peptide hormone (?)

Released by adrenal medulla in response to ‘stress’ (fear, pain, starvation)

Target tissues: muscle, adipose tissue, liver

• Inhibits synthesis of fat, glycogen and protein
• Stimulates breakdown of fat, glycogen and protein

Question 16

Glucose signalling: how it causes insulin production

Answer 16

• Glucose enters pancreatic beta-cells through the glucose transporter - GLUT2
• Glucose then gets broken down via glycolysis and the citric acid cycle to produce ATP
• ATP binds to ATP-gated K⁺ channels, inhibiting them and causing depolarisation
• Depolarisation causes opening of voltage-gated Ca²⁺ channels, resulting in a Ca²⁺ influx
• Ca²⁺ interacts with insulin granules at the endoplasmic reticulum and causes fusion of vesicles with the plasma membrane, resulting in the secretion of insulin

Question 17

Glucagon signalling: how it enters cells

Answer 17

• Binds to receptor (GPCR)
• Gs causes adenyl cyclase to be produced
• ATP is converted to cyclic AMP by adenyl cyclase
• cAMP activates protein kinase A

Question 18

Epinephrine signalling: how it enters cells

Answer 18

• Binds to receptor (GPCR)
• Gs causes adenyl cyclase to be produced
• ATP is converted to cyclic AMP by adenyl cyclase
• cAMP activates protein kinase A

Question 19

Typical intracellular messengers

Answer 19

cAMP, Ca²⁺, IP₃, etc

Question 20

Insulin: how does it send signals to cells and what is the process for it?

Answer 20

Using tyrosine kinase receptor

• Insulin receptor binds insulin and autophosphorylates on its C-terminus tyrosine residues
• Insulin receptor’s tyrosine residues are used to phosphorylate insulin receptor substrates (IRS-1)

IRS-1 can then activate PKB/Akt or MAPK to undergo activating various processes

Question 21

PKB/Akt: what is it, what is it activated by, and what does it do?

Answer 21

Protein kinase B

Insulin/IRS-1

• Phosphorylation of metabolic enzymes (to increase/decrease activity)
• Transcription factors (control of gene expression)
• Activate other regulatory proteins (e.g. phosphatases, translation factors, glucose transporter trafficking)

Question 22

MAPK: what is it, what is it activated by, and what does it act upon?

Answer 22

Mitogen-activated protein kinase

Insulin/IRS-1

Transcription factors

Question 23

cAMP: what is it and what does it do?

Answer 23

Cyclic adenosine monophosphate

• Affects gene expression
• Activates cAMP response element binding protein (CREBP)

Question 24

PKA: what is it and what does it do?

Answer 24

Protein kinase A

• Stimulates gluconeogenesis - Activates FBPase-2, Inhibits pyruvate kinase, and Activates PEP CK
• Stimulates glycogen breakdown - activates glycogen phosphorylase
• Inhibits glycogen synthesis - inhibits glycogen synthase
• Stimulates triacylglycerol (TAG) synthesis - activates HSL, ATGL, and perilipin
• Stimulates FA-oxidation/inhibits FA synthesis - inhibits ACC

Question 25

ATP/AMP as allosteric effectors: what are the typical cellular concentrations of them and why is there a massive difference in potency between them?

Answer 25

ATP ~ 5mM
AMP ~ 0.1mM

A 10% decrease in [ATP] can greatly affect the activity of ATP utilizing enzymes but results in a 600% increase in [AMP] - AMP can be a more potent allosteric effector

(10% of 5mM is 0.5mM, 0.1->0.6mM is a 600% increase )

Question 26

AMPK: what is it, what is it activated by, and what does it do?

Answer 26

AMP-dependent protein kinase

• Increased cellular [AMP]
• Reduced nutrient supply
• Increased exercise
• Sympathetic nervous system
• Leptin, adiponectin, etc

Acts as an ‘energy sensor’, has varying functions in different tissues but the effects lead to the same, main function:
Coordinated change to shift metabolism away from energy processes and increases energy generation by using catabolic pathways

Question 27

MAPK in the heart

Answer 27

Stimulates:
* Fatty acid oxidation
* Glucose uptake
* Glycolysis

Question 28

MAPK in the brain

Answer 28

Stimulates:
* The desire to eat (hunger)

Question 29

MAPK in the liver

Answer 29

Inhibits:
* Fatty acid synthesis
* Cholesterol synthesis
* Glycogen synthesis

Question 30

MAPK in the pancreas

Answer 30

Inhibits:
* beta-cell insulin secretion

Question 31

MAPK in skeletal muscle

Answer 31

Stimulates:
* Fatty acid uptake/oxidation
* Glucose uptake
* Mitochondrial biogenesis

Question 32

MAPK in adipose muscle

Answer 32

Inhibits:
* Fatty acid synthesis
* Lipolysis

Question 33

Glucokinase: what methods of regulation affect it?

Answer 33

• mRNA stability
• Degradation
• Allostery
• Compartmentalisation
• Transcription

Question 34

What are the advantages of using multiple mechanisms for regulation?

Answer 34

• Failsafe mechanism
• Different signals, different mechanisms - can be regulated by various different things
• Allows different speeds of regulation (transcription, long - phosphorylation, quick)
• Allows degree of regulation?