ENDOCRINE SYSTEM: FALL2003

1
ENDOCRINE SYSTEM FALL2003
MARTIN G. LOW, DEPT. PHYSIOLOGY
2
Q WHY DO VERTEBRATES HAVE AN ENDOCRINE SYSTEM?
3
Q WHY DO VERTEBRATES HAVE AN ENDOCRINE SYSTEM?

A ALTHOUGH IT ALLOWS EXTREMELY RAPID
COMMUNICATION THE HARD WIRING OF THE NERVOUS
SYSTEM IS TOO EXPENSIVE, INEFFICIENT (AND
UNNECCESARY) FOR THE DELIVERY OF MOLECULAR
SIGNALS TO EVERY CELL IN THE BODY.
4
THE CARDIOVASCULAR SYSTEM, WHICH IS MOSTLY
DEVOTED TO TRANSPORTING OXYGEN AND NUTRIENTS, CAN
ALSO PROVIDE A HIGHLY EFFICIENT, BUT RELATIVELY
SLOW SYSTEM FOR DELIVERING SOLUBLE MESSENGER
MOLECULES TO ESSENTIALLY EVERY CELL IN THE BODY.

HOWEVER TO ENSURE FIDELITY AND SPECIFICITY OF THE
SIGNALLING PROCESS THESE SOLUBLE MESSENGERS
MUST BE GUIDED TO THE CORRECT DESTINATION BY A
MOLECULAR ADDRESS
5
ENDOCRINE
STIMULUS
1
TRANSPORT VIA BLOODSTREAM TO DISTANT PARTS OF
THE BODY
HORMONE SECRETION
RESPONSE
NEUROCRINE
2
CELL B
TRANSPORT VIA BLOODSTREAM TO DISTANT TARGET
TISSUES
HORMONE
HORMONE
SIGNALLING BETWEEN NEIGHBORING IDENTICAL CELLS
OF SAME TYPE
PARACRINE
AUTOCRINE
3
4
CELL TYPE X
CELL TYPE X
SIGNALLING BETWEEN NEIGHBORING BUT
DIFFERENT CELLS VIA ECF
6
SUMMARY OF THE MAJOR COMPONENTS OF THE ENDOCRINE
SYSTEM


BRAIN
DIET
GnRH
GHRH
TRH
CRH
CALCIUM
GLUCOSE
ACTH
TSH
LH/FSH
PRL
GH

THYROID
BREAST
PANCREAS
PARATHYROID
LIVER
GONADS
ADRENAL CORTEX
IGF-1
PTH
T3 T4
MILK
STEROIDS
GLUCAGON
STEROIDS
INSULIN
ADRENAL CORTEX
TARGET TISSUES
FEEDBACK LOOPS
7
FEEDBACK REGULATION OF PITUITARY HORMONE
SECRETION
BRAIN
RH RELEASING HORMONE
HYPOTHALAMUS
IH
RH
IH INHIBITORY HORMONE
ULTRA SHORT L0OP
LONG LOOP
INDIRECT HOMEOSTATIC SIGNALS? CALCIUM / GLUCOSE
SHORT LOOP
PITUITARY
LONG LOOP
TROPIC HORMONE
THREE DIFFERENT SECRETION MECHANISMS PEPTIDE
STEROID THYROID
PERIPHERAL ENDOCRINE GLAND
HORMONE
TARGET TISSUES
8
STRUCTURE FUNCTION OF MAJOR HORMONES

HORMONE
M.W.
CHEMICAL STRUCTURE
MAJOR FUNCTION
TRIIODOTHYRONINE (T3)
lt1000
GROWTH, METABOLISM DEVELOPMENT
IODINATED TYROSINE DERIVATIVES
THYROXINE (T4)
lt1000
lt1000
''
STEROIDS
CHOLESTEROL DERIVATIVES
ANTI-DIURETIC HORMONE
ARG-VASOPRESSIN (ADH)
(S-S) LINKED CYCLIC NONAPEPTIDES
1000
OXYTOCIN
SUCKLING RESPONSE
1000
STIMULATES RELEASE OF CORTICAL STEROIDS
GLUCAGON
3,500
29-RESIDUE PEPTIDE
PLASMA GLUCOSE
CALCITONIN
4,000
32-RESIDUE PEPTIDE

PLASMA Ca
39-RESIDUE PEPTIDE DERIVED FROM 31K POMC
PRECURSOR
ADRENOCORICOTROPHIC
4,500
HORMONE (ACTH)
51-RESIDUE PEPTIDE WITH (S-S)-LINKED A AND B
CHAINS
PLASMA GLUCOSE
INSULIN
6,000
LIPOLYSIS
PARATHYROID HORMONE
PLASMA CALCIUM
84-RESIDUE PEPTIDE
9,500
LACTOGENESIS
PROLACTIN (PRL)
23,000
198 /191 RESIDUE GLYCOPROTEINS WITH 80
HOMOLOGY
GROWTH HORMONE (GH)
GROWTH / METABOLISM
22,000
GLYCOPROTEINS WITH COMMON ALPHA SUBUNIT AND
VARIABLE BETA SUBUNIT
THYROID-STIMULATING HORMONE (TSH)
28,000
LUTEINZING HORMONE (LH)
30,000

REGULATION OF SPERMATOGENESIS AND OOGENESIS
FOLLICLE-STIMULATING HORMONE (FSH)
30,000
CHORIONIC GONADOTROPHIN (hCG)
57,000
LEPTIN 16kDa 139-RESIDUE PEPTIDE
9
RECEPTOR / HORMONE
a1- ADRENERGIC
a2- ADRENERGIC
10
CELL SURFACE RECEPTORS TRANSDUCERS AND
MESSENGERS? GROUP II
THROMBOXANE A2
THYROTROPIN-RELEASING HORMONE (TRH)
THYROID-STIMULATING HORMONE (TSH)
FOLLICLE-STIMULATING HORMONE (FSH)
PLATELET-DERIVED GROWTH FACTOR (PDGF)
INSULIN -LIKE GROWTH FACTOR 1 ( IGF-1)
NON-RECEPTOR TYROSINE KINASE JAK/Stat
GROWTH HORMONE (GH)
11
HORMONE SECRETION BY THE HYPOTHALAMUS/ PITUITARY
GLAND
NEUROHYPOPHYSIS (POSTERIOR PITUITARY)
ADENOHYPOPHYSIS (ANTERIOR PITUITARY)
HYPOTHALAMUS
NEUROCRINE CELLS
RELEASING AND INHIBITING HORMONES
1
MEDIAN EMINENCE AND NEURAL STALK
SUPERIOR HYPOPHYSEAL ARTERY
2
OXYTOCIN
LONG PORTAL VEIN
ADH
4
3
SHORT PORTAL VEIN
ENDOCRINE CELLS
RETROGRADE FLOW ALLOWS FEEDBACK INHIBITION
INFERIOR HYPOPHYSEAL ARTERY
ANTERIOR PITUITARY HORMONES
GH
TSH
ACTH
LH
PRL
FSH/LH
EFFERENT VEINS
12
CONTROL
AFTER 2 DAY FAST
GH SECRETION IS TIGHTLY COUPLED TO SLEEP PERIOD
MAGNITUDE GREATER DURING PUBERTY
FASTING INCREASES GH SECRETION AND UNCOUPLES
IT FROM SLEEP PERIOD
GH CONCENTRATION
GH SECRETORY RATE
13
PREPROOPIOMELANOCORTIN
265
26

146



ACTH
76
14
STRUCTURAL ORGANIZATION OF MAMMALIAN
PREPROGLUCAGON
MPGF
GLICENTIN
GLP-2 (1-33) -
bioactive
GLUCAGON
GLP-2 (3-33) -
MPGF
bioinactive
GLICENTIN
INTESTINE
OXYNTOMODULIN-1
GLP-1
BRAIN
GLP-2
IP-2
ENTEROGLUCAGONS
15
HORMONES HAVE VARIABLE IN VIVO STABILITY
POTENTIAL REASONS FOR VARIABLE STABILITY
t½
HORMONE
STEROIDS ARE HYDROPHOBIC AND MAY PARTITION INTO
MEMBRANES AND ADIPOSE TISSUE
3h
FSH
70 min
CORTISOL
HORMONE CLEAVED BY SPECIFIC PEPTIDASES IN PLASMA
ALDOSTERONE
70 min
LH
60 min
HORMONE FORMS COMPLEX WITH BINDING PROTEIN WHICH
PROTECTS IT FROM DEGRADATION
I5 min
ACTH
8 min
ADH
SHORT PEPTIDES ARE PARTICULARLY VULNERABLE TO
DEGRADATION BECAUSE THERE ARE FEW CONSTRAINTS ON
THEIR CONFORMATION
5-8 min
INSULIN
3-5 min
OXYTOCIN
16
GnRH PULSE FREQUENCY REGULATES SECRETION OF LH
AND FSH
PORTAL VEIN GnRH
PERIPHERAL CONCENTRATION (ng/ml)
PLASMA LH
DAYS
HOURS
17
INTRACELLULAR RECEPTORSLIGAND-ACTIVATED
TRANSCRIPTION FACTORS
HORMONES WITH INTRACELLULAR RECEPTORS ARE
HYDROPHOBIC ALLOWING DIFFUSION ACROSS PLASMA
MEMBRANE
CONSERVED 240 AMINO ACID HORMONE-BINDING DOMAIN
(STEROIDS ONLY)
HIGHLY VARIABLE TRANSCRIPTION-ACTIVATION DOMAIN
HIGHLY CONSERVED (66 AMINO ACID) DNA-BINDING
DOMAIN CONTAINING TWO ZINC FINGERS
N
CELL SURFACE RECEPTORS REQUIRE TRANSMEMBRANE
SIGNALLING
THIS PROBLEM IS SOLVED BY UTILISING THE ENERGY OF
HORMONE BINDING AT THE CELL SURFACE TO ALTER
CONFORMATION OF TRANSMEMBRANE PROTEINS AND THEIR
INTERACTIONS WITH INTRACELLULAR PROTEINS
POLYPEPTIDE HORMONES ARE HYDROPHILIC AND CANNOT
DIFFUSE ACROSS THE PLASMA MEMBRANE
18
OTHER STEROID HORMONES

ER
TESTOSTERONE (AR)
PROGESTERONE (PR)
ESTROGEN (ER)
GLUCOCORTICOIDS (GR)
1
STEROID HORMONES DIFFUSE ACROSS PLASMA MEMBRANE
STEROID HORMONES BIND TO SPECIFIC, SOLUBLE
INTRACELLULAR RECEPTORS
2
GLUCOCORTICOSTEROID HORMONES BIND TO A SOLUBLE
INTRACELLULAR GR RECEPTOR hsp90 COMPLEX
NUCLEUS
release of inhibitory hsp90 proteins reveals
nuclear localization signal on GR receptor
3
STEROID-RESPONSIVE TARGET GENES
- ve HRE
ve HRE
GRE GLUCOCORTICOID RESPONSE ELEMENT HRE
HORMONE RESPONSE ELEMENT
STEROID RECEPTORS TRANSLOCATE INTO THE NUCLEUS
AND INTERACT WITH GRES, OTHER HREs AND
COACTIVATOR MOLECULES
19
REGULATION OF TRANSCRIPTION BY NON-STEROIDAL
HORMONES
NUCLEUS
NO HORMONES
NO TRANSCRIPTION
HORMONE-RESPONSIVE TARGET GENES
HORMONE-RESPONSIVE TARGET GENES
N
C
RETINOID X RECEPTOR SUBUNIT (RX) REPRESSES
TRANSCRIPTIONAL ACTIVATION BY HORMONE RECEPTOR (R)
PLUS HORMONES
NUCLEUS
TRANSCRIPTION
HORMONE-RESPONSIVE TARGET GENES
VITAMIN D RETINOIC ACID THYROID HORMONE
HRE
HORMONE BINDING RELIEVES REPRESSION BY RETINOID X
RECEPTOR
20
TRANSDUCER COMPLEX
MESSENGER CASCADE
METABOLISM
EXOCYTOSIS
PERMEABILITY
PERMEABILITY
ONE SIGNAL - MANY EFFECTS
MANY SIGNALS - ONE EFFECT
EFFECTS ON CELL FUNCTION MAY ONLY OCCUR IF
CORRECT COMBINATION OF HORMONES ACT
SIMULTANEOUSLY ON SAME CELL
SAME HORMONE MAY HAVE DISTINCT EFFECTS IN
DIFFERENT TISSUES OR CELL TYPES
,
21
TRANSDUCER COMPLEXES
G PROTEIN ADENYLYL CYCLASE G PROTEIN
PLC? RECEPTOR TYROSINE KINASE PLC? RECEPTOR
TYROSINE KINASE IRS-1 RECEPTOR TYROSINE KINASE
Grb2-SoS non-RECEPTOR TYROSINE KINASE (JAK)
METABOLISM
TRANSDUCER COMPLEXES
2ND MESSENGER CASCADES
SECRETION
MESSENGER CASCADES
cAMP PROTEIN KINASE A 1,2- DAG
PROTEIN KINASE C 1P3 Ca2
CALMODULIN Ras
MAP KINASE

EFFECTS ON CELLULAR FUNCTION
OTHER IMPORTANT FEATURES
1. AMPLIFICATION BY ENZYMES OR ION
CHANNELS 2.CROSS-TALK BETWEEN PATHWAYS 3. RAPID
DEGRADATION/ DEACTIVATION OF 2ND MESSENGERS
PERMEABILITY
22
STIMULUS INDUCED DIMERIZATION
G-PROTEIN COUPLED
EGF/ PDGF
EGF/PDGF
TSH BINDING SITE
PDGF
PDGF
SH2 DOMAINS
CELL MEMBRANE
CELL MEMBRANE
SMALL LIGAND BINDING SITE ACCOMODATES
CATECHOLAMINES
G-PROTEIN
-Y-P
P
P
P
P
Autophosphorylation by intrinsic tyrosine kinase
DESENSITIZATION BY ?-ark or pkc

23
GROWTH HORMONE AND PROLACTIN RECEPTORS ARE
LIGAND-INDUCED DIMERS
THE INSULIN RECEPTOR IS A STABLE S-S LINKED DIMER
S-S
-S-S-
-S-S-
-Y-P
IRS-1
TYROSINE KINASE (JAK2)
Stat
IGF-1 USES A SIMILAR MECHANISM
Stat 5A DEFICIENT MICE DO NOT LACTATE
24
GROWTH FACTOR RECPTOR
SIGNAL TRANSDUCTION FROM CELL SURFACE RECEPTORS
TO THE NUCLEUS
---Y-P
TYROSINE PHOSPHORYLATION OF RECEPTOR RECRUITS
Grb2-Sos TO PLASMA MEMBRANE
Grb2
PROTEIN KINASE C
Sos
ACTIVATION OF Ras BY GUANINE NUCLEOTIDE EXCHANGE
FACTOR
GTP
GDP
Ras
Raf/MAPKKK ACTIVATED BY RAS OR PROTEIN KINASE C
ATP
MAPKKK
ADP
MAPKK
ACTIVATION OF MAP- KINASE REQUIRES BOTH THREONINE
AND TYROSINE PHOSPHORYLATION
ATP
MAPK
ADP
NUCLEUS
PHOSPHORYLATION OF TRANSCRIPTION FACTORS IN
NUCLEUS
25
HETEROTRIMERIC G PROTEINS
RECEPTOR ACTIVATION
CYCLASE ACTIVATION
CYCLASE
?
?
?
?
?
?
NUCLEOTIDE EXCHANGE
HIGH INTRINSIC GTPase RAPID DEACTIVATION
Pi
26
Ras AND OTHER SMALL G PROTEINS
SIGNAL IN
GDP
GTP
Sos
NUCLEOTIDE EXCHANGE
Ras (inactive)
Ras (active)

LOW INTRINSIC GTPase

GAP GTPase Activating Protein
SIGNAL OUT
27
MULTIPLE ROLES OF INTRACELLULAR CALCIUM IONS
PI-LINKED RECEPTOR
LIGAND-GATED CALCIUM CHANNEL
VOLTAGE-SENSITIVE CALCIUM CHANNEL
G PROTEIN
PLC
Ca2
Ca2
CALCIUM IS STORED IN THE ENDOPLASMIC RETICULUM
PIP2
2
MYOSIN LIGHT CHAIN KINASE (MLCK)
MULTIFUNCTIONAL CAM KINASES
PHOSPHORYLASE KINASE

PHOSPHORYLASE
EUKARYOTIC ELONGATION FACTOR II
MYOSIN LIGHT CHAIN
28
INOSITOL 1,4,5-TRISPHOSPHATE
HO
HO
OH
HYDROLYSIS
PLC
PHOSPHATIDYLINOSITOLS ARE HYDROLYSED BY
PHOSPHOLIPASE C INTO TWO SECOND MESSENGERS
1,2-DIACYLGLYCEROL
PHOSPHATIDYLINOSITOL

29
PI-4P
PI
PI-4,5P2
PI-3,4,5P3
4-KINASE
5-KINASE
2
6
PI-3KINASE
30
1,2-DAG
PHOSPHATIDYLINOSITOL CYCLE
PI 3,4 -P2
PROTEIN KINASE C ACTIVATION
BIND TO PH DOMAINS
PHOSPHOLIPASE C (PLC) MEDIATED PI HYDROLYSIS IS
STIMULATED BY MANY HORMONES
PI 3,4,5-P3
PI 3-KINASE
INSULIN ACTION
PLC
PI
PI 4-P
PI 4,5-P2
PHOSPHORYLATION
RESYNTHESIS
DEGRADATION
Li
IP2
I
IP
IP3
CALCIUM RELEASE FROM ER VIA LIGAND GATED CHANNEL
Li BLOCKS RESYNTHESIS
31
PHOSPHOLIPASE C ISOFORMS
PLC?
PH
EF
Y
X
N
C2 DOMAIN
C
CATALYTIC SITES
REGULATED BY G?q
EF HAND
PH DOMAIN
REGULATED BY TYROSINE PHOSPHORYLATION
32
SEQUENCE MOTIFS INVOLVED IN SIGNAL TRANSDUCTION
DOMAIN

MOTIF RECOGNIZED
NAME
SH2
src homology 2
pY-X-X-X
phosphotyrosine-binding
- ? -N-P-X-pY-
PTB
proline-rich region
SH3
src homology 3
PH
PI-Px headgroups
Pleckstrin Homology
? Hydrophobic residue
33
ARRANGEMENT OF BINDING DOMAINS AND CATALYTIC SITES
PROTEIN
src kinase
--Myr----SH3----SH3----SH2----Tyr kinase---
Btk
--PH----Pro----SH3----SH2----Tyr kinase----
Shc
--PTB----SH2- (Collagen-like)
Grb-2
--SH3----SH2----SH3
Shp-2 (Syp)
--SH2----SH2----PTPase
?
PLC?
--PH----PLC----PLC--
PLC?
PLC?
--PH----PLC----SH2----SH2----SH3----PLC
--PH----PLC----PLC
PLC?
PKB
--PH---- Ser/Thr kinase
p120Ras-GAP
--SH2----SH3----SH2----PH----GAP
34
LECTURE 3
35
(No Transcript)
36
INSULIN RECEPTOR SIGNALING PATHWAY
INSULIN
GLUCOSE UPTAKE
GLUT4 TRANSLOCATION
PY
PY
SH2
PI 3-KINASE INHIBITORS e.g. WORTMANNIN BLOCK
GLUCOSE UPTAKE
PI 3-KINASE
GLYCOGEN SYNTHESIS
GENE EXPRESSION
FATTY ACID SYNTHESIS
INHIBITION OF LIPOLYSIS
37
SYNTHESIS AND SECRETION OF PEPTIDE HORMONES
9. INCREASED HORMONE SYNTHESIS AFTER CHRONIC
STIMULATION
1.TRANSCRIPTION 2. ALTERNATIVE SPLICING
AGONIST
NUCLEUS
RECEPTOR
mRNA
8. AGONIST-INDUCED, CALCIUM-DEPENDENT EXOCYTOSIS
Ca2
ENDOPLASMIC RETICULUM 3. TRANSLATION 4.
TRANSLOCATION 5. TISSUE-DEPENDENT PROTEOLYTIC
PROCESSING. 6. PACKAGING (200X CONDENSATION)
INTO SECRETORY VESICLES
7. SECRETORY VESICLES ACCUMULATE CLOSE TO PLASMA
MEMBRANE
38
REGULATION OF PLASMA GLUCOSE BY INSULIN AND
GLUCAGON
Pglucose
Pglucose
GLUCOSE - SYNTHESIS - MOBILIZATION
INSULIN t½ approx 5 min
INSULIN SECRETION
PANCREAS ? cell
PARACRINE INHIBITION OF ISLETS OF LANGERHANS BY
INSULIN
GLUCOSE - UPTAKE - UTILIZATION - STORAGE
GLUCAGON t½ approx 10 min
GLUCAGON SECRETION
PANCREAS ? cell
TARGET TISSUES (liver, muscle, adipose, etc.)

39
ISLETS OF LANGERHANS
BLOOD FLOWS RADIALLY FROM CENTER OF ISLET TO THE
PERIPHERY FACILITATING PARACRINE INHIBITION OF
GLUCAGON SECRETION BY INSULIN
1 MILLION ISLETS EACH CONTAINING ?2500 CELLS
CORE FORMED BY BETA CELLS SECRETING INSULIN
(60-70 OF TOTAL)
MANTLE FORMED BY ? CELLS SECRETING GLUCAGON
(20-25)
ARTERIAL BLOOD
Canaliculus
? CELL
? CELL
SECRETORY GRANULES
VENOUS BLOOD
VENOUS BLOOD
40
PHYSIOLOGICAL ROLE OF INSULIN MAINTENANCE OF
NORMAL PLASMA GLUCOSE LEVELS IN SPITE OF LARGE
CHANGES DUE TO FOOD INTAKE
AFTER A MEAL
DURING A FAST
41
K
THESE CHANNELS ARE ALSO SENSITIVE TO OTHER
STIMULI SUCH AS ACETYLCHOLINE AND CATECHOLAMINES
REGULATION OF INSULIN SECRETION BY GLUCOSE
DEPOLARIZATION
Ca2
K
Ca2
ATP/ADP
INSULIN SECRETION
GLUCOKINASE Km 10mM

ATP
UNLIKE HEXOKINASE, GLUCOKINASE IS NOT INHIBITED
BY GLUCOSE-6-P
GLUCOSE
42
RESPONSE OF PLASMA GLUCOSE, GLUCAGON, ACTH AND
GROWTH LEVELS TO INSULIN INJECTION
Pglucose
ACTH
PLASMA GLUCOSE (mg/dL)
GLUCAGON
GROWTH HORMONE
MINUTES
INSULIN INJECTION
43
RESPONSE OF PLASMA INSULIN AND GLUCAGON TO ORAL
GLUCOSE
180
POOR GLUCOSE TOLERANCE
150
Plasma glucose
120
NORMAL GLUCOSE TOLERANCE
PLASMA GLUCOSE (mg/dL)
AVERAGE VALUE
90
plasma insulin
Plasma glucagon
60
30
BELOW 60 mg/dl METABOLISM IS LIMITED BY GLUCOSE
AVAILABILITY
0
1h
2h
3h
4h
5h
44
TISSUE/PLASMA DISTRIBUTION OF GLUCOSE AFTER A MEAL
LIVER GLYCOGEN 75-100g
30g/h
FASTING
PLASMA/ECF 11g
GLUT- 2
10g/h
6g/h
GLUT- 1
10g/h
7g/h
LIVER GLYCOGEN 75-100 g
7g/h
10g/h
GLUT- 2
FED
14g/h

14g/h
0g/h
0g/h
GLUT- 4
GLUT- 4
URINE
45
LIVER
MUSCLE
INSULIN
INSULIN
GLYCOGEN
PROTEIN
AFTER MEAL
GLUCOSE
GLUT4
AMINO ACIDS
GLUCAGON
GLUCOSE
GLYCOGEN
ATP
GLYCOGEN
MUSCLE PROTEIN
DURING FAST
GLUCOSE-6-P
PROTEOLYSIS
GLUT4
GLUCONEOGENESIS LATE IN FAST12-15h
AMINO ACIDS
GLUCOSE
AMINO ACIDS
46
CORTISOL HELPS TO MAINTAIN PLASMA GLUCOSE LEVELS
DURING A FAST BY STIMULATING GLUCONEOGENESIS/LIPOL
YSIS AND INHIBITING LIPID SYNTHESIS
MUSCLE
FATTY ACIDS
PROTEIN
GLUT4
AMINO ACIDS
FATTY ACIDS PROVIDE AN ABUNDANT SOURCE OF ENERGY
BUT IN VERTEBRATES, (UNLIKE PLANTS),THEY CANNOT
BE CONVERTED BACK TO GLUCOSE
IN DIABETES THERE IS NO INSULIN TO INHIBIT THIS
PROCESS
FATTY ACIDS
AMINO ACIDS
GLUT2
GLUT4
GLUCONEOGENESIS
LIPO GLUT4 LYSIS
LIPOLYSIS
GLUCOSE
LIVER
FAT DROPLET
GLYCOGEN
FATTY ACIDS
ADIPOSE
47
DURING A FAST THE LIVER MOBILISES STORED FAT IN
ADIPOSE TISSUE AND CONVERTS IT TO KETOACIDS FOR
EXPORT TO OTHER TISSUES
GLUCOSE
FFA
KETONE BODIES
FFA
MUSCLE HEART etc. ß-OXIDATION OF FATTY ACIDS TO
ACETYL CoA
FFA
FFA
FREE FATTY ACIDS (FFA) HAVE LOW SOLUBILITY AND
ARE TRANSPORTED IN THE BLOOD BOUND TO ALBUMIN OR
LIPOPROTEINS
ADIPOSE TISSUE HYDROLYSIS OF STORED
TRIGLYCERIDES (TG) BY LIPASE
48
DIETARY GLUCOSE
DIETARY FAT
FFA
FFA
AFTER A MEAL THE LIVER SYNTHESIZES FREE FATTY
ACIDS (FFA) FROM GLUCOSE AND EXPORTS IT TO THE
TISSUES AS TRIGLYCERIDES
GLUCOSE CAN BE CONVERTED TO FAT, BUT FAT CANNOT
BE CONVERTED BACK TO GLUCOSE
CAPILLARY ENDOTHELIUM HYDROLYSIS OF TRIGLYCERIDES

MUSCLE, HEART etc. ß OXIDATION OF FATTY ACIDS
ADIPOSE TISSUE RESYNTHESIS AND STORAGE OF
TRIGLYCERIDES
49
REGULATION OF GROWTH HORMONE SECRETION
REM Sleep PGLUCOSE
Arginine
exercise STRESS preREM Sleep
THERE ARE 6 DISTINCT IGF BINDING
PROTEINS IGFBP(1-6) . ONE OF THEM IS THE
EXTRACELLULAR PORTION OF THE GH RECEPTOR
SOMATOSTATIN / GHIH
TRANSPORT IN BLOOD
GHRH
SOMATOMEDIN
GROWTH HORMONE
BASAL GH ? 10-10M TOO LOW TO MEASURE ACCURATELY
SOMATOMEDIN
GROWTH HORMONE IS SPECIES-SPECIFIC
BONE AND CARTILAGE SKELETAL GROWTH EFFECTS
LIVER AND FIBROBLASTS IGF-1 AND IGF-2 SECRETION
MANY TISSUES METABOLIC EFFECTS INCREASED
LIPOLYSIS AND PROTEIN SYNTHESIS DECREASED GLUCOSE
USE
SOMATOMEDIN GHIH IGF-1/1GF-2
50
HORMONAL REGULATION OF METABOLISM
PROTEIN DEGRADATION

PLASMA GLUCOSE
LIVER GLYCOGEN
GLUCOSE SYNTHESIS
LIPOLYSIS
INSULIN
CORTISOL
GLUCAGON
GROWTH HORMONE
(?)
CATECHOLAMINES
(?)
(?-1)
LEPTIN
?
51
REM Sleep
PGLUCOSE
STRESS
REGULATION OF ADRENAL HORMONE SECRETION
CORTISOL
ADDISONS DISEASE DESTRUCTION OF THE ADRENAL
GLAND BY DISEASE OR BY SURGICAL REMOVAL OF THE
GLAND. THIS DISEASE IS LETHAL IF NOT TREATED
BY HORMONE REPLACEMENT THERAPY
CRH
TRANSPORT IN BLOOD
BOUND STEROIDS (90) FREE STEROIDS (10)
ACTH
CORTISOL IS NOT STORED
ALDOSTERONE
ADRENAL CORTEX ZONA FASCICULATA
CHOLESTEROL
STEROIDS
ANDROGEN PRECURSORS
ACTH STIMULATES STEROID SYNTHESIS WITHIN MINUTES
DUE TO CHOLESTEROL ALREADY PRESENT IN
MITOCHONDRIAL INNER MEMBRANE
52
LECTURE 4
53

GLOMERULOSA
CAPSULE
FASCICULATA
ALDOSTERONE
MEDULLA
RETICULARIS
ADRENAL CORTEX
RETICULARIS
CORTISOL

MEDULLA
MEDULLA
ANDROGENS
SECRETION OF INDIVIDUAL STEROID HORMONES IS
RESTRICTED TO SPECIFIC REGIONS OF THE ADRENAL
CORTEX
EPINEPHRINE NOREPINEPHRINE
54
STEROID SYNTHESIS
ALL STEROIDOGENIC TISSUES
CHOLESTEROL (C27)
minus side chain
20-keto

GONADS
- SIDE CHAIN PREGNENOLONE (C21)
PREGNENOLONE (C21)
DEHYDROEPIANDROSTERONE SULFATE (C19 DHEA-S)
3-keto
17-OH
desmolase
sulfotransferase
DEHYDROEPIANDROSTERONE DHEA
17-OH PREGNENOLONE
PROGESTERONE
3-keto
17-OH
3-keto
21-OH
desmolase
11-OH
ANDROSTENEDIONE (C19)
17-OH PROGESTERONE
17-OH PREGNENOLONE
CORTICOSTERONE
21-OH
TESTOSTERONE
aromatase
18-ALDEHYDE
11-OH
3-keto
ESTRONE
aromatase
ALDOSTERONE (C21)
CORTISOL (C21)
ADRENAL CORTEX
ESTRADIOL (C19)
DIHYDROTESTOSTERONE (C19)
55
SYNTHESIS AND SECRETION OF STEROID HORMONES BY
ADRENAL CORTEX
1
CHOLESTEROL IS TAKEN UP INTO MITOCHONDRIA EITHER
DIRECTLY FROM PLASMA LDL/HDL OR FROM
INTRACELLULAR CHOLESTEROL ESTERS STORED IN
LIPID DROPLETS
UPTAKE OF CHOLESTEROL ESTER FROM LDL AND HDL IN
PLASMA
KIDNEY
StAR facilitates transfer of cholesterol
molecules between inner and outer membranes
ALDOSTERONE
2
Cholesterol in Intracellular Lipid droplets
DIFFUSION OF STEROIDS OUT OF CELL
P450scc
StAR
CORTISOL
4
P450c11
11-HYDROXYLASE
11-DEOXYCORTISOL
ANDROGEN PRECURSORS
REMOVAL OF SIDE CHAIN
17-OH PROGESTERONE
ENDOPLASMIC RETICULUM OXIDATION OF STEROID
NUCLEUS BY SPECIFIC P-450 HYDROXYLASES
?5 - PREGNENOLONE (C21)
GONADS
3
56
CHOLESTEROL
? 5-PREGNENOLONE
12
18
17
D
20,22-Desmolase P-450scc
16
11
13
C
1
19
15
4
14
6
9
A
8
2
10

DEHYDROGENASE
B
7
3
5
6
4
17-OH PROGESTERONE
C
O
18
12
18
16
OH
D
11
16
13
C
19
1
1
19
15
14
9
9
2
15
14
8
10
10
9
9
2
A
B
8
10
10
17-HYDROXYLASE
B
7
5
7
O
5
O
6
PROGESTERONE
6
4
57
ANDROSTENEDIONE
ESTRONE
O
O
12
18
12
17
18
D
D
OH
11
16
11
13
13
C
C
19
1
1
19
15
14
17
15
9
14
2
A
9
2
17
A
8
10
10
8
B
B
Aromatase
7
7
5
5
O

HO
6
4
6
4
OH
OH
12
12
18
17
18
D
D
11
11
13
13
C
C
19
1
19
1
15
15
14
14
9
9
2
A
2
A
8
10
10
8
B
B
7
7
Aromatase
5
5
HO
O
6
6
4
ESTRADIOL
TESTOSTERONE
DIHYDROTESTOSTERONE
58
PRE-RECEPTOR REGULATION OF STEROID HORMONE
ACTION
11ß-HYDROXYSTEROID DEHYDROGENASE - (11ß-HSD)
11ß- HSD TYPE 2 (KIDNEY)
11ß- HSD TYPE 1 (LIVER)

40
CORTISOL
CORTISONE
ACTIVE
INACTIVE
OH
CH20H
C
O
12
18
12
18
O
OH
OH
D
OH
D
16
11
13
16
11
11
13
C
19
1
1
19
15
14
15
9
9
14
9
2
A
9
2
A
8
10
10
8
10
10
B
B
B
3 3
3
7
3
7
5
5
O
O
6
4
6
4
59
LOCAL DEHYDROGENATION OF THE C11 HYDROXYL GROUP
ON CORTISOL PROTECTS MINERALOCORTICOID RECEPTORS
(MR) FROM INAPPROPRIATE ACTIVATION
ALDOSTERONEMR
Kd1nM CORTISOL or CORTISONE MR
Kd1nM CORTISOL or CORTISONE GR
Kd10nM
IN SPITE OF THE HIGH AFFINITY OF CORTISOL /
CORTISONE FOR THE MR IN VITRO, GLUCOCORTICOIDS DO
NOT BIND TO MR IN TARGET TISSUES. THIS IS DUE TO
THE PRE-RECEPTOR INACTIVATION OF CORTISOL BY
11ß-HSD2

CORTISOL
CORTISOL
LIVER ADIPOSE GONADS
11ß-HSD2
11ß-HSD1
OXIDATION OF C11 HYDROXYL
CORTISOL
CORTISONE


GR
MR
KIDNEY,COLON SALIVARY GLAND, HEART
nucleus
RESPONSE
NO RESPONSE
nucleus
60
BINDING AFFINITIES OF STEROIDS TO PLASMA PROTEINS


SEX HORMONE BINDING GLOBULIN (SHBG)
CORTISOL BINDING PROTEIN (CBP)
ALBUMIN

HORMONE
CORTISOL
76
1.6
0.003
2.7
CORTISONE
7.8
0.005
ESTRADIOL
0.06
0.06
680
0.06
0.18
14
PREGNENOLONE

8.8
PROGESTERONE
0.06
24
17a -OH-PROGESTERONE
55
0.4
9.9
TESTOSTERONE
1600
0.04
5.3
61

SYNTHESIS OF THYROID HORMONES STEP 1 - IODINATION
HO
Tyr
CH2CHCOOH-
TYROSINE
THYROGLOBULIN
NH2
TYROSINE IODINATION
I

Tyr
THYROGLOBULIN
MONOIODOTYROSINE (MIT)
Approximately 10 of the tyrosine residues on the
550 amino acid residue Thyroglobulin molecule may
become iodinated by the enzyme - thyroid
peroxidase acting on the colloid at the luminal
surface of the thyroid follicle. These reactions
only occur in the thyroid at specific residues in
Hormonogenic sites located at the extreme ends
of the Thyroglobulin molecule.
TYROSINE IODINATION
I
I
HO
DIIODOTYROSINE (DIT)
CH2CHCOOH
Tyr
-
THYROGLOBULIN

NH2
I
62
SYNTHESIS OF THYROID HORMONES STEP- 2 COUPLING
OF IODOTYROSINES
I
HO

HO
HO
CH2CHCOOH
CH2CHCOOH
Tyr
HO
NH2
NH2
I
Thyroglobulin
Thyroglobulin
3,5,35-tetraiodothyronine
Coupling of iodotyrosine moities results in the
loss of the peptide linkage to thyroglobulin
allowing thyroid hormones to diffuse across the
cell membrane
3,5,3-Triiodothyronine
I
I

CH2CHCOOH
HO
CH2CHCOOH
Tyr
HO
O
Tyr
Tyr
NH2
NH2
I
I
Thyroglobulin
I
I
Thyroglobulin
63
I
I
I

CH2CHCOOH
Tyr
Tyr
NH2
NH2
I
I
Thyroglobulin
3,5,35-tetraiodothyronine
STEP 3 DEIODINATION
I
I
I
I

CH2CHCOOH
O
Tyr
Tyr
NH2
I
I
I
I
I
I
T4
ACTIVATION PATHWAY
DEACTIVATION PATHWAY
5-deiodination
5- deiodination
O
Tyr
Tyr
SELENODEIODINASES
rT3
I
I
T
T3
I
I
I
4
I
I
I
I
O
Tyr
Tyr
O
CH2CHCOOH
Tyr
CH2CHCOOH
Tyr
NH2
NH2
Tyr
I
I
3,5,3-Triiodothyronine (T3)
3,3,5-Triiodothyronine (reverse T3)
I
64
SECRETION OF THYROID HORMONE
ENDOCYTOSIS OF COLLOID IN FOLLICLE BY PSEUDOPOD
4
IODINATION OF THYROGLOBULIN BY THYROID PEROXIDASE
TG
TG

3
TG
I
5
FUSION OF PHAGOSOME WITH LYSOSOMES
TG
TG
6
DEGRADATION OF THYROGLOBULIN
DEGRADATION AND RECYCLING OF MIT/DIT BY
DEIODINASES
7
FREE THYROXINE RELEASED FROM PROTEIN INTO
CYTOPLASM
T4
2
8
Other monovalent anions compete with iodide for
uptake sometimes with useful medical and
experimental applications e.g. TCO4Cl04 SCN
IODIDE UPTAKE BY Na/I SYMPORTER
DIFFUSION OF THYROXINE THROUGH CELL MEMBRANE
gt
gt
gt
T4
T3
Additional metabolism??
IODIDE IN ECF20nM
1
65
THYROID HORMONES
99.7
0.3
66
EFFECTS OF THYROID HORMONE ON TARGET TISSUES
MOST EFFECTS OF THYROID HORMONE ARE
PERMISSIVE THYROID HORMONE PROMOTES SYNTHESIS
OF PROTEINS WHICH ARE THEN REGULATED ACUTELY BY
OTHER HORMONES.
THYROID DISEASES
METABOLISM THYROID HORMONE INCREASES BASAL
METABOLIC RATE BODY TEMPERATURE CARDIAC OUTPUT/
TACHYCARDIA MOBILIZATION OF ENERGY STORES
CONGENITAL HYPOTHYROIDISM DUE TO METABOLIC
DEFECT IN THYROID HORMONE SYNTHESIS RESULTING IN
MENTAL RETARDATION UNCOMMON IN DEVELOPED
COUNTRIES DUE TO EARLY POST- NATAL TESTING
ENDEMIC HYPOTHYROIDISM DUE TO IODIDE DEFICENCY
OR GOITROGENS. READILY PREVENTED BY IODIDE
SUPPLEMENTATION OF FOOD
GROWTH AND DEVELOPMENT THYROID HORMONE REQUIRED
IN PERINATAL PERIOD FOR NEURAL DEVELOPMENT
BONE GROWTH (GH)
HYPERTHYROIDISM AUTOIMMUNE GRAVES DISEASE
PITUITARY TUMOR THYROID TUMOR WEIGHT LOSS
67
THYROID DISEASES
AUTOIMMUNE GRAVES DISEASE
UNREGULATED SYNTHESIS AND SECRETION OF T3 AND T4
UNREGULATED SYNTHESIS AND SECRETION OF TSH
68
CALCIUM IN DIET
PLASMA Ca2
CALCIUM SENSOR DECREASE IN PLASMA CALCIUM
STIMULATES PARATHYROID HORMONE (PTH) SECRETION
CHOLESTEROL
PARATHYROID
VITAMIN D3
PTH
25-(OH)-D3
PTH
PO4
GUT
BONE
KIDNEY
1,25-(OH)2-D3
Ca2
CALCIUM REABSORPTION PHOSPHATE EXCRETION
PO4
BONE RESORPTION
CALCIUM ABSORPTION via CALBINDINS
Ca2
Ca2
BONE DEPOSITION
URINE
99 IN BONE OF WHICH 50 IS BOUND TO PROTEINS.
lt1 IN ECF ltO.1 IN ICF
INCREASE IN PLASMA CALCIUM STIMULATES CALCITONIN
SECRETION FROM THYROID PARAFOLLICULAR CELLS
PLASMA Ca2
69
100
PTH SECRETION EXHIBITS A STEEP INVERSE SIGMOIDAL
DEPENDENCE ON EXTRACELLULAR Ca2
INCREASED Ca2 SUPRESSES PTH SECRETION VIA A G
PROTEIN COUPLED MECHANISM
50
MAXIMAL PTH RESPONSE
0
1.0
1.5
1.25
IONIZED CALCIUM (mM)
70
CALCITONIN IS SECRETED FROM THE THYROID
PARAFOLLICULAR CELLS
BUT IS CALCITONIN AN IMPORTANT PHYSIOLOGICAL
SUBSTANCE?
The observation that calcitonin (CT) at
supraphysiological doses is hypocalcemic, led to
the mistaken conclusion that it was important for
calcium homeostasis and this idea has persisted
to this day. Despite these findings there is no
readily apparent pathology due to CT excess or
deficiency and there is no evidence that
circulating CT is of substantial benefit to any
mammal. .. . Mammalian CT at
physiological doses is not essential and very
likely the CT gene has survived because of the
genes alternate mRNA pathway to produce
calcitonin-gene-related peptide found in neural
tissues. HIRSCH,PF and BARUCH H, ENDOCRINE
2003, 201-208