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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