Unfed state: Glucagon signaling, glycogen breakdown, and fatty acid mobilization

Lecture 2

Identify hormone secreted during fasting (unfed) state

Glucagon

• Released by pancreas when blood glucose is low

• goes to two main areas:

  • Liver

  • Adipose Tissue

In Liver:

Pathway activated & its Goal

• Glycogen breakdown - Release Glucose

• Gluconeogenesis - Produce Glucose

• Produce ketones

In Adipose Tissue

PA and Goal:

Lipolysis (Triglycerol Breakdown) - Fatty Acid & Glycerol Release

Describe pathways activated during fasting state & where each process occurs

Glycogenolysis: Liver

• Glycogen → Glucose 6-P : 3 steps

Gluconeogenesis: Liver

Lipolysis: Adipose

Differentiate between glycogen stored in muscle vs liver.

2. Describe how the body uses liver glycogen compared to muscle glycogen

Background:

• Glycogenin— a protein that primes glycogen synthesis

  • tiers of glucose residues: in (a1-4) linkage, with (a1 →6)-linked branches

  • glycogenin is the center, the tiers are the branches stemming outward… each chain has 12 to 14 residues;)

Liver Glycogen: responsible for restoring blood glucose levels to normal levels upon glucagon signaling

Muscle Glycogen: stores are mobilized to provide energy for muscle contraction

• NOT released in response to low blood glucose levels

Steps of Glycogen Breakdown (Glycogenolysis)

First Step: Phosphorolytic Cleavage

Glycogen Phosphorylase cleaves off glucose at the end by Phosphorlysis

• releases glucose 1-phosphate molecule (G 1-P)

• Advantage of phosphorlysis - energy is saved for cells by using the energy of the alpha 1-4 bond instead of ATP to add phosphate to glucose

• Acts repeatedly until reaching a point four glucose residues away from a (a1→6) branch point

Second: Debranching

Transfers branches onto main chains, releases the residue at the (a1→6) branch as free glucose

• happens when a branch is reached.

Third Step: G1P → G 6-P

Phosphoglucomustase converts G1P to glucose-6-phosphate (G69)

• the rapid release of G 1-P favors isomerization rxn to form Glucose 6-P

  • PO3 on C-1 moves to C-5

  • reaction is reversible (depends on conc. of substrates)

Fourth Step: Fate of G6-P from Glycogen breakdown: muscle cell vs. liver cells

• Muscle Cell: enter glycolysis to supply energy (ATP) to cells

• Liver Cell: the phosphate can be removed, allowing free glucose to be transported out of the cell to replenish levels of circulating blood glucose

  • can be used in the brain and other tissues when dietary glucose is not sufficient

Steps of the signaling cascade:

• starting with glucagon (or epinephrine)

• ending with activation of glycogen phosphorylase (glycogen breakdown in liver cells)

When blood glucose drops…

1. Glucagon binds receptor to activate PKA, which activates glycogen breakdown in liver cells

   1. Receptor:

      1. a-subunit of the G protein is the binding site of GDP and GTP

   2. Receptor activates adenylyl cyclase, converts ATP to cyclic AMP (cAMP) → activates PKA

      1. Inactive PKA: Catalytic subunit is attached to regulatory subunits

      2. Active PKA: Catalytic subunits detach after 4 cAMP, and become active

   3. PKA phosphorylates and activates phosphorylase kinase

      1. Proteins typically phosphorylated on hydroxyl groups of Ser, Thr, or Tyr

How glycogen phosphorylase stimulates breakdown of glycogen into glucose

Post translation modification modulates its activity

How glycogen phosphorylase is regulated

Post-translational modification:

Allosteric regulation

• AMP activates glycogen phosphorylase (esp. are in muscle)

• ATP and glucose-6-P inhibit it (feedback inhibition)

Phosphorylation state:

• Phosphorylated form (active) form is GPa

• Dephosphorylated form (less/inactive) form is glycogen phosphorylase b (GPb)

Describe the signaling cascade initiated by glucagon (or epinephrine) stimulates breakdown of fat (triacylglycerol) into fatty acids acids

How the glucagon signaling cascade is turned off

Can be shut down in multiple ways':

1. Receptor interaction is reversible

2. Ga has inherent GTPase activity that cleaves the bound GTP to GDP

3. cAMP phosphodiesterase converts cAMP to AMP, stopping PKA activation

Difference between a reaction catalyzed by a kinase (e.g. Protein Kinase A) versus
glycogen phosphorylase

Kinase vs Phosphorylase:

Kinase

Function: adds phosphate group to a molecule

PO3 Source: ATP

Role: regulates enzyme activity

Rxn Type: Phosphorylation

Ex: PKA (phosphorylates enzyme)

Phosphorylase

Function: breaks bonds using inorganic phosphate (Pi), especially in glycogen

PO3 Source: Pi (inorganic phosphate)

Role: Breaks down molecules like glycogen

Rxn Type: Phosphorolysis

Ex: Glycogen phosphorylase, which removes glucose from glycogen

Lipolysis

• Glucagon signaling activates PKA

• PKA activates lipase via phosphorylation

• Active lipase catalyzes hydrolysis of triacyglycerols to free fatty acids

• Fatty acids transport

Epinephrine release in exercise

Epinephrine, a hormone, is release from adrenal glands that bind to receptors found on

• Liver

• Fat (adipocytes)

• Muscle cells

signals to

• Breakdown glycogen in the muscle and liver

• Breakdown triacylglycerols in fat cells

Glycogen is a substrate for which of the following and is directly converted to monosaccharide units?

1. GPCR

2. glycogen phosphorylase

3. glucose-6-phosphatase

4. Protein kinase A

Answer: glycogen phosphorylase

During fasting, liver cells use which type of 'fuel molecule' to generate energy (ATP)?

1. Ketones

2. Fatty Acids

3. Glucose

4. Acetyl-CoA

Fatty Acid