Hormones and Regulation of Metabolism

Question 1

Diagram an overview of metabolic pathway interactions between organs

Question 2

Describe the metabolic demands of specific tissues - brain, red blood cell, heart, muscle, kidney, liver, adipose tissue?

Answer 2

Brain, CNS -> uses only glucose OR KB after ~48hrs starvation

Red blood cell -> uses only glucose

Heart -> uses both glucose AND FA, but prefers FA

Muscle -> uses everything + KB; stores everything; supplise lactose and amino acids

Kidney -> uses everything + KB; stores everything; supplies everything

Liver -> uses everything; stores everything; supplies everything + KB

Adipose tissue -> uses FA, glucose; stores TAG; supplies FA + glycerol

“everything” = glucose, fatty acids, and amino acids

Question 3

Describe key tissues in normal energy metabolism - Liver

Answer 3

Supplies: glucose, ketone bodies, fatty acids

Stores: glucose (glycogen), fatty acids (TAGs)

Uses everything (DOES NOT USE KB), supplies everything

Question 4

Describe key tissues in normal energy metabolism - Muscle

Answer 4

Supplies: lactate, amino acids

Stores: glucose (glycogen), fatty acids (TAGs)

“selfish” - glycogen, TAG stores for own use

Question 5

Describe key tissues in normal energy metabolism - Adipose Tissue

Answer 5

Supplies: fatty acids, glycerol

Stores: fatty acids (TAGs)

Question 6

How are these metabolic interactions among organs coordinated?

Answer 6

Problem: complicating factors such as: variable diet (varies DAILY), variable needs (daily variations in activities); organ specialization: various organs/tissues have specific needs/roles

Solution: hormonal regulation

Question 7

Hormonal Regulation of Metabolism - General characteristics, major classes of hormones, principles of action of the hormones

Answer 7

General: small signal -> large effect (biologic amplification)

Major classes:

• polypeptide hormone, ex: insulin and glucagon
• amino acid derivative, ex: epinephrine
• steroid, ex: cortisol
• eicosanoid hormones, ex: prostaglandins

Principles of action:

• effective at low concentrations -> amplified -> secondary signals -. target
• tissue specific: due to specific receptors on the various tissues
• different responses in different tissues: due to different receptor types; different isozymes respond to the signals
• self-limiting activity: due to rapid breakdown of the hormone (i.e. t1/2 = 5min for glucagon)

Question 8

Insulin structure

Answer 8

Synthesized (RER) as: preproinsulin (inactive)

To Golgi as: proinsulin (inactive)

• lost leader (aka signal) sequence [via a protease] in rough ER

Released as: insulin (active)

• t1/2 = 5mins
• C-peptide (connecting peptide) - removed (again via a protease), but not degraded, and is released with insulin

* more stable, longer half life than insulin

* used for diagnostic purposes in early diabetes

Question 9

Insulin Secretion and Receptor

Answer 9

Secretion - in response to HIGH BLOOD SUGAR from beta-cells of the pancreas

Receptor: ‘receptor-as-kinase’

structure of the insulin receptor: 2 alpha-subunits bind insulin; 2 beta-subunits cytosoilc domains are tyrosine kinases

Activation: insulin binds to extracellular alpha-subunits -> causes an intracellular conformational change of the receptor -> activates kinase domains

Rapid autophosphorylation of a specific tyrosine residue on each beta-subunit occurs

The autophosphorylated tyrosine kinase domains of the insulin receptor induce a cascade of cell-signaling responses - phosphorylate a family of proteins called insulin receptor substrates (IRS); ultimately activates phosphatases (cleave off phosphate groups); the phosphatases then dephosphorylate target proteins

Question 10

General Rule of Insulin

Answer 10

Insulin dephosphorylates target proteins to typically ACTIVATE them

Insulin “Dp” ACTIVATES

• ex: HMG-CoA reductase, glycogen synthase, pyruvate dehydrogenase complex - all are active in the dephosphorylated state
• Exception: glycogen phosphorylase - dephosphorylated form is INACTIVE* [note: the exception is the enzyme’s ‘activity’ - not its phosphorylation state]

Question 11

Insulin Target Tissues - Liver?

Answer 11

Synthetic processes and glycolysis [store excess sugars as TAGs]: STIMULATED

Gluconeogenesis/glycogen breakdown: INHIBITED (decrease glucose production - because liver doesn’t need to export glucose if plenty in blood already)

Question 12

Insulin Target Tissues - Muscle?

Answer 12

Glucose uptake into muscle cells: STIMULATED

Synthetic processes (glycogen synthesis, sprotein synthesis, etc): STIMULATED

Question 13

Insulin Target Tissues - Adipose Tissue?

Answer 13

Glucose uptake: STIMULATED

TAG synthesis (and other synthetic processes): STIMULATED

Question 14

Downstream Effects of Insulin - Promotes?

Answer 14

Fuel uptake - glucose, TAG (i.e. fatty acids from chylomicrons and VLDLs), amino acids

Synthesis - TAG, glycogen, protein, cholesterol

Glucose metabolism - glycolysis in the liver (store excess glucose as fat)

Question 15

Downstream Effects of Insulin - Inhibits?

Answer 15

Gluconeogenesis - in the liver

Glycogen breakdown - in the liver

Lipolysis - in adipose tissue; insulin is a potent inhibitor of lipolysis, even at very low insulin concentrations

Protein degradation - in muscle

Question 16

Insulin Overall Effect on Plasma Levels

Answer 16

Glucose - Decrease (cells are taking glucose & liver removing excess glucose from blood)

Fatty Acids - Decrease

Amino Acids - Decrease

Ketone Bodies - Decrease

Question 17

Insulin In General

Answer 17

Associated with FED STATE; acts to STORE ENERGY (acts as a ‘growth hormone’ because stimulates synthesis of many biological molecules)

Question 18

Beckwith-Weideman Syndrome

Answer 18

increase insulin -> decrease glucose in blood -> hypoglycemia

Question 19

Glucagon Structure

Answer 19

Synthesized (RER) as: preproglucagon (inactive)

To Golgi as: proglucagon (inactive)

• a protease cleaves off 20 amino acids from amino-terminus

Released as: glucagon (active)

• a protease cleaves off 8 amino acids from carboxy-terminus
• t1/2 = 5mins

Question 20

Glucagon Secretion

Answer 20

In response to LOW BLOOD SUGAR from alpha-cells of the pancreas

Secretion mechanism - complex

• self-limiting reaction - as insulin produced, a signal to alpha-cells inhibits glucagon secretion

Question 21

Glucagon Receptor

Answer 21

A Gs-protein coupled receptor

Mechanism of signal transduction:

Glucagon binds to the receptor and activates the receptor -> activates a Gs-Protein (GTP bound) -> releases Gs alpha-subunit (now active) -> the active Gs alpha-subunit -> activates adenylate cylcase -> increase cAMP -> activates protein kinases -> phosphorylate target proteins -> typically INACTIVATES the target proteins

Question 22

General Hormone Rules

Answer 22

Insulin DEPHOSPHORYLATES target proteins to typically ACTIVATE them

• Ex: HMG-CoA reductase, glycogen synthase, pyruvate dehydrogenase complex - all are active in the dephosphorylated state

Glucagon PHOSPHORYLATES target proteins to typically INACTIVATE them

• Ex: HMG-CoA reductase, glycogen synthase, pyruvate dehydrogenase cmoplex - all are inactive in the phosphorylated state

Exceptions: glycogen phosphorylase and fructose 2,6-bisphosphatase (FBP2)

• dephosphorylated forms are INACTIVE
• phosphorylated forms are ACTIVE

Question 23

Target tissues and downstream effects of glucagon - Liver?

Answer 23

Glucagon Promotes:

Gluconeogenesis; glycogen breakdown; ketone body synthesis (releases H2O soluble fuel sources to the blood)

Glucagon Inhibits:

Glycolysis; glycogen synthesis

Question 24

Target tissues and downstream effects of glucagon - Adipose Tissue?

Answer 24

Glucagon Promotes:

• lipolysis (provides FAs to liver for ketone body synthesis)

Glucagon Inhibits:

• lipogenesis (TAG synthesis)

NOTE: glucagon does NOT act on muscle tissues

Question 25

Glucagon In General

Answer 25

Associated with STARVED STATE; acts to promote glucose synthesis and fatty acid mobilization to promote ketone body synthesis to ensure water-soluble fuel sources available for all tissues