Endocrinoimmunologic features of obese children 

,

Research Institute of

Interventional Allergology and Immunology, Bonn/Cologne, Germany

Prof. Dr. Alireza Ranjbar

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

Obesity in Children and teens Obesity in Children and teens

- In recent years the prevalence of obesity in children and In recent years the prevalence of obesity in children and teens has significantly increased in developed and teens has significantly increased in developed and underdeveloped countries. underdeveloped countries.

- In accordance with KiGGS study (study of Robert-Koch-Institute for health of children and teens in Germany:

- - 15% of children and teens are 15% of children and teens are overweightoverweight

- 6,3% are - 6,3% are obeseobese

- 3% suffers from - 3% suffers from arterial hypertensionarterial hypertension

- 210 children and teens develope per year - 210 children and teens develope per year diabetes diabetes mellitus type 2mellitus 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 andIL- 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 Complement-Related 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

Macrophage

Proinflammatory Cytokines

Oxygen free radicals

Oxygen free radicals in obesity ( A. Ranjbar )

Endocrinologic and metabolic disorders

Adipocytes

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

OH-

Organic 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

Macrophage

IL-1IL-6

IL-8

TNF-alphaGM-CSF

Oxygen free radicals

Schematic outline of the role of Macrophageand oxygen free radicals in AIT with

hypothyroidism( A. Ranjbar )

Thyroid tissue damage / impairment of iodidetransport in the thyroid follicle / inhibition ofTPO activity and thyroide hormon formation

Free radicals , Thyroid peroxidase and DeiodinasesFree radicals , Thyroid peroxidase and Deiodinases

- Free radicals block the iodine uptake and iodine Free radicals block the iodine uptake and iodine transpost into the thyroide follicles.transpost into the thyroide follicles.

( Fukamaya H., et al. 1991 )( Fukamaya H., et al. 1991 )

- Free radicals (ROS) inhibit the activity of Thyroid Free radicals (ROS) inhibit the activity of Thyroid peroxidase(TPO). peroxidase(TPO). ( Sugawara M. et al., 2002( Sugawara M. et al., 2002) )

Thyroid peroxidase (TPO)Thyroid peroxidase (TPO)

- Thyroid peroxidase (TPO) is a type I glycosylated Thyroid peroxidase (TPO) is a type I glycosylated transmembrane protein with a molecular weight of 100 transmembrane protein with a molecular weight of 100 KD.KD.

- It catalyzes iodide oxidation, iodination of tyrosineIt catalyzes iodide oxidation, iodination of tyrosine

residues and coupling of iodotyrosines to generateresidues and coupling of iodotyrosines to generate

the iodothyronines T4 and T3. the iodothyronines T4 and T3.

Thus, TPO plays a key role in thyroid hormone Thus, TPO plays a key role in thyroid hormone biosynthesis and is essential for biosynthesis and is essential for normal thyroid functionnormal thyroid function

Free radicals , Thyroid peroxidase and DeiodinasesFree radicals , Thyroid peroxidase and Deiodinases

- Free radicals inhibit the activity of deiodinases.Free radicals inhibit the activity of deiodinases.

( Brezezinska-Siebodzinska E. et al. 1997 , Huang TS., et al. 1987)( Brezezinska-Siebodzinska E. et al. 1997 , Huang TS., et al. 1987)

Free radicals , Thyroid peroxidase and DeiodinasesFree radicals , Thyroid peroxidase and Deiodinases

- The deiodinasea are the enzymes which The deiodinasea are the enzymes which converts T4 to T3 in the peripheral tissues. This converts T4 to T3 in the peripheral tissues. This process takes place mainly within the cells.process takes place mainly within the cells.

- During this process about 80% of plasma T3 is During this process about 80% of plasma T3 is synthesized synthesized

- They metabolize rT3, which is biologically - They metabolize rT3, which is biologically inactive to 3,3´-T2, which is then utilized in the inactive to 3,3´-T2, which is then utilized in the resynthesis of thyroid hormones . resynthesis of thyroid hormones .

Free radicals , Thyroid peroxidase and DeiodinasesFree radicals , Thyroid peroxidase and Deiodinases

- TSH regulation is controlled via T3 in the TSH regulation is controlled via T3 in the respective nucleus of the pituitary gland. respective nucleus of the pituitary gland.

- From a pathophysiological point of view, an From a pathophysiological point of view, an intracellular reuction of T3 will lead to a feed-intracellular reuction of T3 will lead to a feed-back with a consecutive rise in TSH.back with a consecutive rise in TSH.

Hypothalamus(TRH)

T4 T35´-DI type II

Pituitary gland(TSH)

T4 T35´-DI type II

Thyroid gland(T4, T3)

T4 T35´- DI type I

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e f

ee

db

ac

k

Negative feedback

Negative feedback

Pathway of Thyroid Hormone Metabolism andRegulation (Ranjbar A., Pizzulli A.)

Peripheraltissues

T4 T35´-DI type I,II

AntioxidantsAntioxidants

Antioxidants („Scavenger“)Antioxidants („Scavenger“)

Vitamins-A -C -E

etc ...

Carotinoids- -Carotin- -Carotin- Lycopin - Lutein- Zeaxanthin- ...

Trace elements- Selenium as cofactors

- Iron - Copper- Zinc - Mangan

Phytoestrogens- Isoflavonoide- ...

Enzyme- Catalase- SOD Superoxiddismutase- Glutathion peroxidase- ...

Polyphenole- Phenolic acid- Flavonoids- ...

Sulfide- Allicin- ...

FreeFreeRadicalsRadicals

Antioxidants

The best synergy between antioxidants in nature is found in plant foods, which are rich in micronutrients and phytochemicals.

S ynergie!

Ubichinon

Vitamin C

Vitamin E

M n SO D-

Sperm inSperm id in

SAM

GST( , , , )

M DA

8-OHdG m t

DNS

X-R

XR-GSH

M ethioninCystein

NAC-L iponsre

HNEPGF2

8-OHdGnkLD L

ATP

Cu,Zn SOD-

CATALASE

RO S

GSH

GSSG

GPXGR

© B ie g e r 0 5 /2 0 0 0

Synergismus of nature

100 gr fresh apple contins approx.

5,7 mg Vit C

The antioxidative capacity

is equal to

1500 mg synthetic Vit CNature 2000, 430: 903-4

The antioxidativeThe antioxidative capacity of 100gcapacity of 100gapple (5,7mg Vit. C)apple (5,7mg Vit. C)Is equal to 1500 mg Is equal to 1500 mg synthetic vitamin Csynthetic vitamin C

total oxyradical-scavenging capacity(TOSC; mol vitamin C equivalents per g)

Nutrition: Antioxidant activity of fresh applesMARIAN V. EBERHARDT1, CHANG YONG LEE1 & RUI HAI LIU1

Department of Food Science, 108 Stocking Hall, Cornell University, Ithaca, New York 14853-7201, USANature 405, 903 - 904 (June 22th, 2000)

A pilot study

Influence of pulv. fruit / vegetablesin children with overweight

(Ranjbar A , Pahl S, 2006)

1

75

60

45

30

15

>30 portions fruit/vegetables/W

( n=0)

Nume

r of p

atien

tsThe consumption of fruit / vegetables

in children with overweight(n=82)

32

5-10 portions fruit/vegetables /W

( n=12)

<5 portions fruit/vegetables/W

( n=70)

188

170

10

8

6

4

2Weig

ht re

ducti

on%

mea

n +/-

SD

The weight reduction in percent before and after substitution with pulverised fruit and vegetables

in children with overweightvs. control group (Ranjbar A, Pahl S)

20

p < 0.01

20

20

Without substitutionn=24

Substitutionn=22

after 4 wks

80

160

10

8

6

4

2

before

VA

S,

mean

+/-

S

D

The physical ability and excercise before and aftersubstitution with pulverised fruit and vegetables usingvisual analog scale (VAS) in children with overweight

vs. control group (Ranjbar A, Pahl S)

78

70

p < 0.01

20

20

Without substitutionn=24

Substitutionn=22

after 4 wks

160

68

10

8

6

4

2

before

VA

S,

mean

+/-

S

D

Desire for sweets before and after substitutionwith pulverised fruit and vegetables using

visual analog scale (VAS) in children with overweightvs. control group (Ranjbar A, Pahl S)

160

168

p < 0.01

20

20

Without substitutionn=24

Substitutionn=22

after 4 wks

90

160

10

8

6

4

2

before

VA

S,

mean

+/-

S

D

The quality of life before and after substitutionwith pulverised fruit and vegetables using

visual analog scale (VAS) in children with overweightvs. control group (Ranjbar A, Pahl S)

92

82

p < 0.01

20

20

Without substitutionn=24

Substitutionn=22

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 sindIm menschlichen Organismus konnten bisher drei PPAR-Subtypen (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.

165

78

25

20

15

10

5

before

mcg

/l, me

an +/

- SD

Leptin levels before and after weight reduction in children with adipositas

(Ranjbar A., Quade A)

160

p < 0.01

20

20

Adipositas, malen=28

Adipositas, femalen=30

after 12 wks

Control groupn=20

p < 0.01

Conclusion;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

ConclusionConclusion

- 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