Transcript Free radicals , Thyroid peroxidase and Deiodinases The

3rd international congress of the
International Prof. Dr. Alireza Yalda Academic Foundation in Medical Sciences
27-30 November 2012, Tehran, Iran
The recent outcomes research in molecular and clinical medicine
and the role of medical ethics and social responsibilities
Endocrinoimmunologic features of obese children
Prof. Dr. Alireza
Ranjbar
,
Research Institute of
Interventional Allergology and Immunology,
Bonn/Cologne, Germany
Obesity in Children and teens
- In recent years the prevalence of obesity in children and
teens has significantly increased in developed and
underdeveloped countries.
- In accordance with KiGGS study (study of Robert-KochInstitute for health of children and teens in Germany:
-
15% of children and teens are overweight
6,3% are obese
3% suffers from arterial hypertension
210 children and teens develope per year diabetes
mellitus type 2
The human fatty tissue
The human fatty tissue is not just a passive organ to save
the excessive energy or serves as heat insulation, but
produces as an active endocrine unit the biologically
active substances, called Adipokine
Human fatty tissue and immune system
The human fatty tissue contributes to the innate immune
system and plays an important role in the immunology of
infection.
It contains adipocytes, pre-adipocytes, fibroblasten and
macrophages .
Adipocytes and immune system
The adipocytes are able to detect foreign antigenes via specific
receptors on their cell surface and releases proinflammatory
cytokines and acute phase proteins like tumor necrosis factor α
(TNF α), interleukin 6 (IL 6), C-reaktives protein (CRP), plasminogen
activator inhibitor-1 (PAI-1), vascular cell adhesion molecule-1
(VCAM-1), p-selektin, serum amyloid A3, fibrinogen or
angiotensinogen.
Therefore, adipocytes are involved in systemic inflammation.
Macrophage in obesity
In addition to adipocytes the human fatty tissue has a lot of
macrophages which play a crucial role in inflammation.
Under physiological condition CD14 and CD31 positive macrophages
amount to 5-10% of stroma cells of fatty tissues.
The number of macrophages in fatty tissue correlates positively with
BMI and the size of adipocytes.
In obese patients the amount of macrophages increases up to 60% in
fatty tissue especially in visceral fatty tissue compared to
subcutanous fatty tissue.
Macrophage and obesity
In obeses patients the increase of infiltration in the fatty tissue is
induced by monocytes and precursor cells from bone marrow under
the influence of increased production of Monocyte Chemotactic
Protein-1 (MCP-1) and Colony Stimulating Factor-1 (CSF-1).
Marophages are the major origin for production of TNF-alpha and
IL- 6 which lead to insulin resistance.
The expression and secretion of TNF- alpha correlate with body
weight.
TNF-alpha and diabetes
TNF-alpha disturbs insulin signal and leads to insulin resistance
by reduction of phosphorylation of insulin receptor substrat-1
(IRS-1) and disturbance of synthesis and translocation of glucose
transporters type 4(GLUT-4).
The pathogenesis of diabetic complications like retinopathy,
nephropathy, neuropathy and atherosklerosis attributes to the
enhanced local accumulation of activated macrophages.
On the other hand the increased glucose levels and oxidated low
density lipoprotein (LDL) activate the phogocytes and lead to
local tissue damages by production and secretion of
inflammatory and cytotoxic metabolits.
The extent of local damages correlates positively with the levels
of glucose in blood.
Chronic inflammation in obesity
Summarized, an increase of BMI ist correlated wíth significant
secretion of proinflammatory cytokines from adipocytes and
macrophages of fatty tissues, particularly in abdomen.
In mouse model it could be shown a positive correlation between
increase of weight and enhancement of expression of mRNA
transcript inflammatory genes in fatty tissue. The weight reduction
leads significantly to decrease of systemic ciculationg inflammatory
molecules in serum.
Therefore, obesity is a mild chronic inflammation which is associated
with pathogenesis of cardiovascular diseases and diabetes mellitus
type 2.
Adiponektin
Adiponektin
Adiponektin was discovered in 1996 by Maeda et al. and called
adipose most abundant gene transcript 1 (apM1) or because of its
structure homology complement factor C1q as Adipocyte ComplementRelated Protein of 30 kDa (ACRP30) .
Adiponektin is a peptide hormone and produced only by the
diffrentiated adipocytes of fatty tissue. Its synthesis is induced during
the maturation process of preadipocytes to end diffrentiated
adipocytes by Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ).
The serum concentartion of adiponektin in human is between 3-30
µg/ml.
Property of adiponektins
Adiponektin acts
- antidiabetic,
- antiatherosclerotic and
- antiinflammatory
- A decrease of adiponektin levels in serum is often associated with
metabolic syndrome.
Influence of function of human monocytes by adiponektin
Adiponektin
- inhibits the production of proinflammatory mediators like IL 6, TNF α
and Interferon γ (IFN γ)
- increases the release of antiinflammatory molecules like IL10 by
reduction of translocation of Nuclear Factor κB (NF-κB) unit p65, one of
the important regulators of cytokine expression in nucleus of cells.
- downregulates macrophage scavenger receptors-A (MSR-A) which
regulates the intracellular engery and induction of apoptosis.
Free oxygen radicals in obesity
Oxygen free radicals in obesity ( A. Ranjbar )
Macrophage
Adipocytes
Proinflammatory
Cytokines
Oxygen free radicals
Endocrinologic and metabolic disorders
Free oxygen radicals (reactive oxygen species=ROS)
ROS are atoms, molecules or residues which carry single electrones
in the outer membane. They possess a great potential to damage the
vital cells because of reaction with proteins, lipids and DNA.
Die important ROS in the biological systems :
Singulett-Oxygen (1O2)
Superoxide anions (O2- )
H2O2
OHOrganic peroxide (ROOH)
Cell damages by ROS
Aus: “Free Radicals
Randox Ltd.
Free oxygen radicals have negative effect on
- physical and psychological condition
-immune system and
- DNA
and play a central role in the pathogenesis of
mitochondrial dysfunction, cell damages, metabolic
disorders, arterial hypertension and diabetes mellitus
type 2.
Free radicals and thyroid
Schematic outline of the role of Macrophage
and oxygen free radicals in AIT with
hypothyroidism( A. Ranjbar )
Macrophage
IL-1
IL-6
TNF-alpha
GM-CSF
IL-8
Oxygen free radicals
Thyroid tissue damage / impairment of iodide
transport in the thyroid follicle / inhibition of
TPO activity and thyroide hormon formation
Free radicals , Thyroid peroxidase and Deiodinases
- Free radicals block the iodine uptake and iodine
transpost into the thyroide follicles.
( Fukamaya H., et al. 1991 )
- Free radicals (ROS) inhibit the activity of Thyroid
peroxidase(TPO). ( Sugawara M. et al., 2002)
Thyroid peroxidase (TPO)
- Thyroid peroxidase (TPO) is a type I glycosylated
transmembrane protein with a molecular weight of 100
KD.
- It catalyzes iodide oxidation, iodination of tyrosine
residues and coupling of iodotyrosines to generate
the iodothyronines T4 and T3.
Thus, TPO plays a key role in thyroid hormone
biosynthesis and is essential for normal thyroid function
Free radicals , Thyroid peroxidase and Deiodinases
- Free radicals inhibit the activity of deiodinases.
( Brezezinska-Siebodzinska E. et al. 1997 , Huang TS., et al. 1987)
Free radicals , Thyroid peroxidase and Deiodinases
- The deiodinasea are the enzymes which
converts T4 to T3 in the peripheral tissues. This
process takes place mainly within the cells.
- During this process about 80% of plasma T3 is
synthesized
- They metabolize rT3, which is biologically
inactive to 3,3´-T2, which is then utilized in the
resynthesis of thyroid hormones .
Free radicals , Thyroid peroxidase and Deiodinases
- TSH regulation is controlled via T3 in the
respective nucleus of the pituitary gland.
- From a pathophysiological point of view, an
intracellular reuction of T3 will lead to a feedback with a consecutive rise in TSH.
Pathway of T hyroid Hormone M etabolism and
Regulation (Ranjbar A., Pizzulli A.)
Pituitary gland
(T SH)
T4
T3
5´-DI type II
T hyroid gland
(T 4, T 3)
T4
T3
5´- DI type I
Peripheral
tissues
T4
T3
5´-DI type I,II
Negative feedback
Negative feedback
Negative feedback
Hypothalamus
(T RH)
T4
T3
5´-DI type II
Antioxidants
Antioxidants („Scavenger“)
Vitamins
etc ...
Enzyme
-A -C -E
- Catalase
- SOD Superoxiddismutase
- Glutathion peroxidase
Carotinoids
-  -Carotin
-  -Carotin
- Lycopin
- Lutein
- Zeaxanthin
- ...
Trace elements
- Selenium
Free
Radicals
as cofactors
- ...
Sulfide
- Allicin
- ...
Phytoestrogens
- Isoflavonoide
- ...
Polyphenole
- Iron - Copper
- Phenolic acid
- Zinc - Mangan - Flavonoids
- ...
Antioxidants
The best synergy between antioxidants in
nature is found in plant foods, which are rich in
micronutrients and phytochemicals.
Synergie!
Ubichinon
XR-GSH
Vitamin E
GST( ,,,)
ROS
Vitamin C
-
X-R
Cu,Zn SOD
Mn- SOD
CATALASE
LDL
8-OHdGnk
ATP
DNS
Methionin
Cystein
Spermin
Spermidin
NAC
-Liponsre
GSH
GR
GSSG
© Bieger 05/2000
HNE
MDA
PGF2
SAM
GPX
8-OHdG
mt
Synergismus of nature
100 gr fresh apple contins approx.
5,7 mg Vit C
The antioxidative capacity
is equal to
1500 mg synthetic Vit C
Nature 2000, 430: 903-4
Nutrition: Antioxidant activity of fresh apples
MARIAN V. EBERHARDT1, CHANG YONG LEE1 & RUI HAI LIU1
Department of Food Science, 108 Stocking Hall, Cornell University, Ithaca, New York 14853-7201, USA
Nature 405, 903 - 904 (June 22th, 2000)
The antioxidative
capacity of 100g
apple (5,7mg Vit. C)
Is equal to 1500 mg
synthetic vitamin C
total oxyradical-scavenging capacity
(TOSC; mol vitamin C equivalents per g)
A pilot study
Influence of pulv. fruit / vegetables
in children with overweight
(Ranjbar A , Pahl S, 2006)
The consumption of fruit / vegetables
in children with overweight
(n=82)
75
Numer of patients
60
1
8
8
45
30
15
32
1
>30 portions
fruit/vegetables/W
( n=0)
5-10 portions
fruit/vegetables /W
( n=12)
<5 portions
fruit/vegetables/W
( n=70)
The weight reduction in percent before and after
substitution with pulverised fruit and vegetables
in children with overweight
vs. control group (Ranjbar A, Pahl S)
10
Without substitution
n=24
20
Substitution
n=22
20
p < 0.01
8
Weight reduction%
mean +/- SD
6
4
17
0
2
20
after 4 wks
The physical ability and excercise before and after
substitution with pulverised fruit and vegetables using
visual analog scale (VAS) in children with overweight
vs. control group (Ranjbar A, Pahl S)
Without substitution
n=24
20
Substitution
n=22
20
10
p < 0.01
VAS, mean +/- SD
8
6
160
4
2
80
7
8
before
70
after 4 wks
Desire for sweets before and after substitution
with pulverised fruit and vegetables using
visual analog scale (VAS) in children with overweight
vs. control group (Ranjbar A, Pahl S)
Without substitution
n=24
Substitution
n=22
10
p < 0.01
VAS, mean +/- SD
8
6
4
2
160
1
6
0
before
16
8
68
after 4 wks
20
20
The quality of life before and after substitution
with pulverised fruit and vegetables using
visual analog scale (VAS) in children with overweight
vs. control group (Ranjbar A, Pahl S)
Without substitution
n=24
20
Substitution
n=22
20
10
p < 0.01
VAS, mean +/- SD
8
6
4
2
90
9
2
before
16
0
82
after 4 wks
Peroxisom-Proliferator-aktivierte Rezeptoren (PPARs)
Peroxisom-Proliferator-aktivierte Rezeptoren (kurz:
PPARs) sind intrazellulare Rezeptoren, die über einen
physiologischen oder pharmakologischenLiganden aktiviert
werden und als Transkriptionsfaktoren die Expression einer
Vielzahl von Genen regulieren. Sie gehören zu einer Gruppe
von Rezepzoren, die im Zellkern angesiedelt sind
Im menschlichen Organismus konnten bisher drei PPARSubtypen (α, β/δ, γ) identifiziert werden. Diese
unterscheiden sich nicht nur in ihrer lokalen Expression,
sondern vor allem auch hinsichtlich ihres
Genexpressionsmusters und der biologischen Funktion der
Gene, deren Transkription durch sie beeinflusst wird.
Peroxisom-Proliferator-aktivierte Rezeptoren
PPARγ wird ubiquitär exprimiert. Die Aktivierung von PPARγ
bewirkt insbesondere eine Verbesserung des
Glucosestoffwechsels sowie der Insulinsensitivität. Weiterhin
steigert die Aktivierung des PPARγ-Rezeptors die Aufnahme
freier Fettsäuren und wirkt auf die Differenzierung von
Adipozyten und Makrophagen. Darüber hinaus hat auch die
Aktivierung von PPARγ antiinflammatorische Effekte.
Letztlich konnte eine Assoziation zwischen der Aktivierung
des PPARγ-Rezeptors und einer Reduktion des
Atherosklerose-Risikos gezeigt werden.
Leptin levels before and after weight reduction
in children with adipositas
(Ranjbar A., Quade A)
Adipositas, male
n=28
Adipositas, female
n=30
25
Control group
n=20
mcg/l, mean +/- SD
20
15
10
5
165
1
6
0
before
p < 0.01
p < 0.01
78
after 12 wks
20
20
Conclusion;
- Obesity is a complex chronic disease with high comorbidity and
complications.
- The following factors may be involved in its pathogenesis
-
Genetics
Endocrine and metabolism
Immune system
Environment
Education
Economy
Psychosocial and education statues
Eat behaviour pattern
Conclusion
- Because of complexity of obesity an interdisciplinary teamwork is
needed to take care of these patients and treat or prevent
optimally the complcations of this disease.
Thank you
for your attention