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BCH3120: GENERAL INTERMEDIARY METABOLISM

LECTURE 20, APRIL 5
LUC POITRAS, [email protected]

Lecture 20 : Hormonal regulation

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Second midterm
 Review session
 Thursday, April 6th from 9 to 11am.
 STM464

 If you can’t make it, it will have to be during my office

hours next week.
 Wednesday and Thursday
 2-3:30pm
 BSC104
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Final exam
 Structure
 15 MCQs
 10 true or false
 9 short answer questions
 5 long answer questions
 1 Bonus question
 I won’t answer any question regarding this bonus
question
 You will need a calculator for the exam.
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Review session
 Wednesday, April 12th from 8:30 to 10am.
 Zoom meeting.
 A link will be provided on Brightspace.
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Endocrine glands
 Hypothalamus/pituitary gland:
 Control of appetite and stress
 Adipocytes*
 Secrete adipokines (appetite,
metabolic activity,…)

 Adrenal glands:
 Secrete catecholamines
(epinephrine, norepinephrine)

 Pancreas:
 Secretion of glucagon (catabolic)
and insulin (anabolic)
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CATABOLIC hormones
(glucagon)
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Glucagon

 Secreted by pancreatic alpha cells

 Restores blood glucose levels (receptor expressed
mainly in liver, kidney and adipose tissue)
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Hormonal signalling (catabolic hormone)

1. Hormone binds to a G-protein-coupled receptor

 G-proteins are guanine-nucleotide binding proteins
 Heterotrimeric complex (Gα, β and γ)
 Gα can bind GDP or GTP (active when bound to GTP)
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Hormonal signalling (catabolic hormone)

2. Binding of the hormone to its receptor leads to a change in

conformation of the receptor that allows the recruitment of
the G-proteins complex.
3. This interaction allows the exchange of the GDP located on
the Gα subunit for a new molecule of GTP.
 The Gα -GTP complex detaches from the G-protein complex.
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Hormonal signalling (catabolic hormone)

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Hormonal signalling (catabolic hormone)

4. Adenylyl cyclase (also called adenylate cyclase) is activated

by binding of the active Ga (loaded with a GTP).
 The enzymatic activity of adenylyl cyclase take places in the
cytoplasm.
 Adenylyl cyclase catalyzed the conversion of ATP into cyclic AMP
(cAMP)
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Hormonal signalling (catabolic hormone)

 Cyclic AMP or cAMP is a second messenger important for

many biological processes.
 Regulation of glycogen, carbohydrates and lipids metabolism
 cAMP is an activator of PKA (Protein kinase A)
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Hormonal signalling (catabolic hormone)

5. cAMP molecules bind to the regulatory subunits of PKA.

 PKA is composed of two catalytic and two regulatory subunits.
 In absence of cAMP, the regulatory units inhibit the activity of the
catalytic subunits.
 Binding of cAMP to the regulatory subunits of PKA causes a change
in conformation in these subunits
 The change in conformation release the catalytic subunits.
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Hormonal signalling (catabolic hormone)

The free catalytic subunits of PKA are now activated and can
phosphorylated key regulating enzyme implicated in various
metabolic pathway.
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Hormonal signalling (catabolic hormone)

 To restrict the effect of cAMP, excess cAMP is converted to

AMP by members of the phosphodiesterase (PDE) family.
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Hormonal signalling (catabolic hormone)

Summary

1. Catabolic hormone receptors are coupled to G-proteins

2. Binding of the hormone leads to activation of the receptor
3. Receptor activation is mediated by the G-protein
4. Upon activation, the Gα monomer dissociates
5. Gα diffuses and activates adenylate cyclase (AC)
6. Adenylate cyclase converts ATP to cAMP
7. cAMP activates the cAMP-dependent protein kinase A (PKA)
8. PKA phosphorylates target regulatory enzymes
9. Phosphodiesterase (PDE) converts cAMP into AMP in order to
attenuate the catabolic effect
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Hormonal regulation of the metabolic

pathways
 Questions to be answered:
 What is the key regulatory enzyme of the…
 ...glycogen synthesis pathway?
 ...glycogen breakdown pathway?
 ...glycolysis pathway?
 ...gluconeogenesis pathway?
 ...fatty acid synthesis?
 ...fatty acid breakdown?
 What is the effect of glucagon on these regulatory
enzymes?
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Glucagon signalling: Glycogen

 Synthesis and Breakdown of glycogen

 Identify the key regulatory enzyme for each pathway:

 glycogen synthase [glycogen synthesis)]

 glycogen phosphorylase [glycogen breakdown)

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Glycogen synthesis and breakdown

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Glucagon signalling: Glycogen

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Glucagon signalling: Glucose

 Synthesis and Breakdown of glucose

 Identify the key regulatory enzyme for each pathway:

 PFK and Pyruvate Kinase [glycolysis]

 FBPase-1 [gluconeogenesis]
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Glycolysis and gluconeogenesis

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Regulation of the synthesis and

degradation of fructose-2,6-bisphosphate
in liver
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Glucagon signalling: Glucose (1)

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Glucagon signalling: Glucose (2)

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Glucagon signalling: Lipids

 Synthesis of lipids (FAs and cholesterol)

 Identify the key regulatory enzyme for each pathway:

 Acetyl-CoA carboxylase (ACC) [FAs]

 HMG-CoA reductase [Cholesterol]

 Perilipin and HSL [FAs release from TAG]

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Lipogenesis / Ketogenesis
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Glucagon signalling: Lipogenesis/Ketogenesis

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Cholesterol Biosynthesis
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Glucagon signalling: Cholesterol biosynthesis

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TAG homeostasis
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Glucagon signalling: TAG homeostasis

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Glucagon signalling: TAG homeostasis

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Complete the table

Glucagon regulates the following pathways:
Metabolic effect Target enzyme

↑ glycogen breakdown (liver, muscle) ↑ glycogen phosphorylase

↓ glycogen synthesis (liver, muscle) ↓ glycogen synthase

↓ glycolysis (liver, muscle) ↓ PFK1 (via PFK2/FBPase2);

↑ gluconeogenesis (liver) ↑ FBPase1 (via PFK2/FBPase2);

↑ mobilization of fatty acids (AT) ↑ HSL

↑ ketogenesis and β-oxidation ↓ acetyl-CoA carboxylase (ACC)

↓FAs and cholesterol synthesis ↓ ACC and HMG-CoA reductase

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Glucagon
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ANABOLIC hormones
(Insulin)
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Insulin signalling (anabolic hormone)

 Insulin receptor is composed of

two extracellular a subunits and
two transmembrane b subunits
linked by disulphide bonds.

1. The binding of insulin to its receptor leads to a

change in conformation resulting in the
autophosphorylation of the receptor (tyrosine
residues)
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Insulin signalling (anabolic hormone)

2. Phosphorylated tyrosines are recognized by

members of the Insulin Receptor Substrate family
(mainly IRS1 and 2)
3. This binding triggers the phosphorylation of
tyrosine residues on IRS proteins
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Insulin signalling (anabolic hormone)

4. Phosphorylated IRS proteins are recognized by

PI3-kinase (Phosphatidylinositol-4,5-bisphosphate
3-kinase)
5. This binding leads to the activation of PI3K, which
in turn phosphorylates PIP2 to make PIP3.
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PIP2 and PIP3 are membrane lipids

derived from PI

Figure 6.19 The biology of Cancer, Garlang Science 2007

 PI= phosphatidyl-inositol
 PIP2= phosphatidyl-inositol-(4,5) diphosphate
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PIP2 and PIP3 are membrane lipids

derived from PI

Figure 6.19 The biology of Cancer, Garlang Science 2007

 PIP3= phosphatidyl-inositol-(3,4,5) triphosphate

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Insulin signalling (anabolic hormone)

6. Akt/PKB is recruited to the membrane by PIP3

where it will be phosphorylated by PDK1 (3-
phosphoinositide-dependent protein kinase 1).
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Phosphorylation of Akt/PKB by PDK1

Figure 6.19 The biology of Cancer, Garlang Science 2007

 PIP3= phosphatidyl-inositol-(3,4,5) triphosphate

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Insulin signalling (anabolic hormone)

6. Once activated, Akt/PKB is released from the

membrane. It will access the cytoplasm, where it
will phosphorylate and inactivate GSK-3 (glycogen
synthase kinase-3).
7. Akt/PKB will also phosphorylate and activate PDE
(phosphodiesterase), accelerating the conversion
of cAMP into AMP.
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Insulin signalling (anabolic hormone)

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Insulin signalling: Glycogen

 Synthesis and Breakdown of glycogen

 Identify the key regulatory enzyme for each pathway:

 glycogen synthase [glycogen synthesis]

 glycogen phosphorylase [glycogen breakdown]

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Glycogen synthesis and breakdown

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Insulin signalling: Glycogen

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Insulin signalling: Glucose

 Synthesis and Breakdown of glucose

 Identify the key regulatory enzyme for each pathway:

 FBPase-1 [gluconeogenesis]

 PFK [glycolysis]

 GLUT4 [glucose uptake]

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Insulin signalling: Glucose

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Insulin signalling: Glucose (uptake)

 Binding of insulin leads to the translocation of the

glucose transporter GLUT4 to the membrane.
 Where is this translocation occurs?
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Insulin signalling: Lipids

 Synthesis of lipids

 Identify the key regulatory enzyme for each pathway:

 Acetyl-CoA carboxylase [FAs synthesis]

 HMG-CoA reductase [Cholesterol synthesis]

 cAMP, LPL [FAs storage]

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Insulin signalling: Fatty acid synthesis

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Insulin signalling: Cholesterol synthesis

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Insulin signalling: TAG synthesis

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Complete the table

Insulin regulates the following pathways:
Metabolic effect Target enzyme

↓ glycogen breakdown (liver, muscle) ↓ glycogen phosphorylase

↑ glycogen synthesis (liver, muscle) ↑ glycogen synthase

↑ glycolysis (liver, muscle) ↑ PFK1 (via PFK2/FBPase2);

↓ gluconeogenesis (liver) ↓ FBPase1 (via PFK2/FBPase2);

↓ mobilization of fatty acids (AT) ↓ HSL, cAMP

↑ FAs and cholesterol synthesis ↑ ACC and HMG-CoA reductase

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Summary: Insulin & Blood Glucose

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Insulin
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Hormones & Stress

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Hormones & Stress

Adrenal glands

kidneys
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Physiological & Metabolic Effects of stress