Download Regulation of Organic Metabolism, Growth, and

Metabolism
The goal of this lectures is to discuss basic
physiology associated with the control of
metabolism, such as the neuroendocrine
control of pre- and post- absorptive states.
The sections for this lecture are:
22
Introduction
Neuroendocrine control of metabolism Insulin and Glucagon
Growth hormone(GH) and growth factors (IGF)
Thyroid hormones (tri / tetra iodotyronin,T3 and T4)
Catecholamines (Cas, Epi and Norepinephrine)
Glucocorticoids (Cortisol in humans)
Major metabolic pathways of the absorptive state Major metabolic pathways of Life is a series of chemical reactions occurring in
compartmentalized environments. The main purpose of life is to keep itself alive
Physiology, the study of how life works, is based on
the simultaneous occurrence of the following three
concepts:
levels of organization
structure / function relationship
homeostatic regulation
the post - absorptive state Introduction
central integration center
afferent
receptor
S
E
the endocrine system
plays a predominant
role in the
neuroendocrine
control of metabolism
efferent
effector
negative feedback signal
1
Introduction
FUEL METABOLISM IN ANABOLIC / CATABOLIC PHASES
State
Hormones Fuel
Process
Source
anabolism
Insulin
diet
Glycogen synthesis
Triglyceride synthesis
Protein synthesis
storage
depots
Glycogenolysis
Lipolysis
Proteolysis
Ketogenesis
Glucagon
catabolism
Insulin
Glucagon
Introduction
2
Introduction
glycogen phosphorilase
glycogen
glycogen synthetase
G-1-P
G-6-Pase
glucose
hexokinase
glucose
G-6-P
F-6-P
F-1,6-diPase
PFK
F - 1,6 -diP
transaminases
insulin
glucagon
epinephrin
cortisol
triose
amino acids
pyruvate
proteins
Krebs
cycle
acetyl CoA
fats
Introduction
Absortive
State
3
Introduction
Post - Absortive
State
Introduction
4
Introduction
Introduction
5
Introduction
The main endocrine systems involved in the
neuroendocrine control of metabolism are
Introduction
6
Insulin
Insulin
• 51 aa, 2 chains, 3 disulfide bonds, C-peptide
• stimulates anabolism and favors energy storage
• increases glycogen storage and inhibits both
glycogen breakdown and gluconeogenesis
• increases fatty acid synthesis and decreases
lipolysis and ketogenesis
• stimulates transport of glucose and of some
aminoacids into striated muscle / adipose tissue
• increases protein synthesis in liver, muscle,
adipose
• like growth factors, has a growth promoting effect
7
Insulin
Insulin
Tyr-P of docking protein
IRS - 1
Cys rich
hydrophobic aa
kinase
insulin
NH2
ECF
memb
ICF
COOH
SH2domain
mediated
complex
formation
Ser - Thr
kinase
cascade
DNA
synthesis
and gene
transcription
SOS
ras
raf
MEKK
MAPK
phosphatidyl
inositol -3 -P
stimulation
of
glucose
transport
p90rsk
PP1G
glycogen synthase
8
Insulin
Cys rich
hydrophobic aa
kinase
insulin
NH2
ECF
memb
ICF
COOH
Insulin
CHIEF ACTIONS OF INSULIN ON METABOLIC PATHWAYS
glycogenolysis
gluconeogenesis
phosphorylase (glucose-dependent de-P)
PEPCK (transcriptional regulation) FDPase-2 (enzyme dephosphorylation)
ketogenesis
substrate (alanine) delivery from muscle
glycogen synthesis
fatty acid synthesis
substrate (FFA) delivery from fat
glycogen synthase (enzyme de-P)
acetyl CoA carboxylase (transcription)
fatty acid synthase
Muscle
proteolysis
protein synthesis
glucose uptake
glycogen synthesis
multiple mechanisms
activity at multiple steps
recruit Glut-4 to cell surface
glucose uptake
glycogen synthase (enzyme de-P)
Fat
lipolysis
hormone sensitive lipase (enzyme de-P) triglyceride
synthesis
delivery of tryglyceride from liver lipoprotein
lipase
Liver
9
Insulin
Insulin
10
Insulin
Insulin
11
Anti insulin controls
Glucagon
12
Glucagon
• the main counterregulator to insulin together with
catecholamines (epinephrine) & cortisol
• 29 aa, member of a family of related peptides that
includes VIP, GIP, and secretin
• determines glycemia in postabsorptive state through
glycogenolysis and gluconeogenesis
• glucose, insulin and SS inhibit its release
• aa, exercise and CAs stimulate its release
• gene expression is restricted to cells in islet and is
negatively regulated by insulin
• glycentin, GI specific proteolytic processing
Glucagon
glucagon
R
cell membrane
Gs AC
phosphodiesterase
ATP ----------> cAMP -----------------------------------> 5’AMP
inactive PKA ----------> active PKA
inactive PKb <----------> active PKb
glycogen phosphorilase b <----------> glycogen phosphorilase b
glycogen + Pi ----------> glucose - 1 - P
cell membrane
T
blood glucose
13
Glucagon
CHIEF ACTIONS OF GLUCAGON ON METABOLIC PATHWAYS
LIVER
glycogenolysis
glycogen phosphorylase (cAMP-dep-P)
glycogenesis
glycogen synthase (phosphorylation)
F - 1,6 - diPase (phosphorylation)
gluconeogenesis
pyruvate kinase (phosphorylation)
glycolysis
substrate delivery, releasing inhibition
of carnitine palmytoil transferase,
allowing mitochondrial transfer and FA
oxidation
ketogenesis
Glucagon
Glucagon
and Glucose
Metabolism
Glucagon
and Fat
Metabolism
Glucagon
and Protein
Metabolism
14
Glucagon
Insulin / Glucagon
15
Growth Hormone
Growth Hormone
•
•
•
•
•
•
•
•
lowers blood aminoacid concentrations
lowers blood urea nitrogen. Positive N
balance
increases DNA, RNA, and protein synthesis
elevates glycemia by decreasing CH utilization
and the sensitivity to the insulinhypoglycemic effect
elevates fat oxidation. Lowers respiratory
quotient
induces growth in general mostly through
IGFs
stimulates growth and calcification of
cartilage (IGFI)
GH abuse causes diabetes mellitus by
exhaustion of ß-cells overstimulated by high
glycemia (meta- hypophyseal diabetes).
Impaired glucose tolerance in acromegaly
might be related to this interaction
16
Growth Hormone
chemical
stimuli
hypothalamus
ultra
short
loop
GHRH
SS
negative
feed-back
anterior pituitary
stress
centers
sleep
centers
long
loop
negative
feed-back
GH
liver
short
loop
negative
feed-back
GHRH-BP
GH - BP
& DHT
somatomedins or IGF
tissues
Growth Hormone
• the GHRH peptide:
• G - protein linked receptor
• AC/cAMP, PLC / IP, PLA/
PGE
• sexual dimorphism (DHT)
• have receptors for SS
• the SS peptide:
• G - protein linked receptor
• Gi, AC, open K channels,
hyperpolarization, lower Ca
influx to cell
seven transmembrane
domain receptor
NH
2
ECF
plasma
memb
G
ICF
COOH
GDP
enzyme
GTP
channel
17
Growth Hormone
MUSCLE
LIVER
prot synthesis
RNA synthesis
gluconeogenesis
aa uptake
prot synthesis
glucose uptake
increased
muscle mass
ADIPOSE
glucose uptake
lipolysis
SM production
IGF - I
chondrocytes of bone
collagen synthesis
protein synthesis
cell proliferation
increased linear growth
decreased
adiposity
IGF - II
many organs and tissues
protein synthesis
RNA synthesis
DNA synthesis
cell size and number
increased tissue growth
and increased organ size
Growth Hormone
• GH receptors do not have a kinase
• Dimerization, if GH excess inhibition
• Ligand binding results in rapid
phosphorylation of cell proteins on Tyr
• Janus (JAK) kinases are cytoplasmic
tyrosine kinases which physically
associate with the box 1 - box 2 domains
of the ligand bound receptor leading to
auto - phosphorylation on Tyr residues
and phosphorylation of transcription
factors called “signal transducers and
activators of trans-cription” or in short
“STATS”
• Most GH effects are mediated by IGFs
kinase
Cys residues
hydrophobic aa
GH
JAK2
DNA
STAT
18
Growth Factors
Cys residues
• GFs have Tyr-K except
TGFß which phosphorilates Ser / Thr residues
• receptor dimerization
• amplification through
multiple kinases & stats
(signal transducers and
activators of
transcription)
• long-term effects of GFs
are dependent on shifts
in gene expression
kinase
hydrophobic aa
Cys rich
GFs-BP
as local
storage
also ?
IGF II
EGF PDGF
NH2
insulin
IGF I
COOH
JAK2
STAT
GH
Prl
cytokines
Thyroid Hormones
19
Thyroid Hormones
Major Functions of the Thyroid Hormones
Thyroid Hormones
20
Thyroid Hormones
TRH and TSH
NH
2
ECF
plasma
membrane
G
ICF
GDP
COOH
enzyme
GTP
channel
Thyroid Hormones
T3 / T4
21
Thyroid Hormones
TSH
R
AC
(tyrosin) T
cAMP
MIT
pump
(tyronine) DIT
I-
2
I
I-
2
T3
I
T4
TBG
TBPA
albumin
T3
T4
protease
lysosome
colloid
droplet
t
h
y
r
o
g
l
o
b
u
l
i
n
Thyroid Hormones
T3 / T4
Na / K
ATPase
22
Thyroid Hormones
DNA
binding
region
NH
2
1
Hormone
binding
region
COOH
Structure
of nuclear
hormone
receptors
563
estrogen
1
946
1
777
1
glucocorticoid
917
thyroid
hormone
androgen
427
Vitamin D
408
1
progesterone
1
Thyroid Hormones
empty
binding
site
inactive
co-repressor
COOH
T3R
T3R
HRE
TFIIB
TATA box
RNAPol II
DNA
co-repressor
COOH
T3
active
T3R
T3R
HRE
TFIIB
TATA box
RNAPol II
DNA
23
Thyroid Hormones
500
500
T3
Pituitary extract + T4
body
weight
(g)
increased
metabolism
(ml O2/100g/h)
pituitary
extract
300
T4
300
normal
Tx + T4
100
thyoidectomy, Tx
100
0
100
200
dose of thyroid hormone
0
100
200
time in days
Catecholamines
24
Catecholamines
Catecholamines
25
Catecholamines
Catecholamines
• Epi, NE, Ach, DA, glucagon
seven transmembrane
• Gs (ß1,ß2), Gi (2), Gq (1)
domain receptor
• adrenoreceptors are upregulated in
NH
the absence of stimulation and
2
ECF
downregulated under continuous
stimulation (eg. denervation
plasma
supersensitivity vs continuous
membrane
isoproterenol)
G
• adrenoreceptor responses to Cas
ICF
are affected by gonadal steroids
GDP
COOH
(eg.uterine contraction due to CAs
in E2 vs P4 mileau)
enzyme
• cortisol is permissive for cAMP
GTP
metabolic and pressor effects
channel
• T3 & sympathoadrenal activity
26
Catecholamines
• under stress blood glucose should be elevated for energy
production by brain, heart, skeletal muscle
• Epi stimulates hepatic glycogenolysis (ß receptor)
• muscle glycogen, lactic acid, liver (gluconeogenesis)
• Cas inhibit insulin / stimulate glucagon (ß receptor)
• hypoglycemia stimulates adrenal Epi secretion by a CNS
glucoreceptor (blocked by anesthetic in hypoth)
• Epi stimulates lipolysis by + HS-lipase and TG-lipase
• FFA used as energy source (glucose-sparing action)
• Epi decreases muscle proteolysis and aa release which
might be of physiological importance to its short-term
response associated with stress (ß recept)
Glucocorticoids
27
Glucocorticoids
Glucocorticoids
Effect of Cortisol on Organic Metabolism
28
Glucocorticoids
• increases
gluconeogenesis by a
genomic mechanism
• inhibits glucose
transport thus
decreases its utilization
• reduces aa use for
protein formation
except in the liver
• increases FA / glycerol
mobilization from
adipose depot
Glucocorticoids
Zn fingers are binding regions of transcription factor proteins
which attach to the promotor segment of DNA
G
H
G
R
R
HSP 90
HSP 90
Zn
G
H
G
H
R
R
Zn
Zn
HRE
HSP 90
TATA
box
RNA
Pol II
DNA
HSP 90
29
Glucocorticoids
gluconeogenesis and glucocorticoids
• increase synthesis of gluconeogenic enzymes
within hepatocytes (anabolic)
• actions on skeletal muscle and adipose are
catabolic (block glucose uptake, stimulate
proteolysis, lipolysis, and promote FFA and
glycerol mobilization)
• glucose produced is either stored as glycogen or
released into the blood
• excessive secretion is antagonistic to insulin and
promotes diabetes mellitus, an effect that is
amplified since they reduce the affinity of certain
cells for insulin, further aggravating the diabetes
ZG
ZF
ZR
Metabolism
30
Absorptive State
Absorptive State
31
Postabsorptive State
Postabsorptive State
32