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Hypothesis:

Hypothesis:. AN ECTOPIC SYNTHESIS OF THE MELANIN IN ADIPOSE MAY HELP TO COUNTERACT SECONDARY COMPLICATIONS OF OBESITY. Manpreet Randhawa, Tom Huff, Julio C. Valencia, Zobair Younossi, Vikas Chandhoke, Vincent J. Hearing, Ancha Baranova. Why obesity is so dangerous ?.

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Hypothesis:

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  1. Hypothesis: AN ECTOPIC SYNTHESIS OF THE MELANIN IN ADIPOSE MAY HELP TO COUNTERACT SECONDARY COMPLICATIONS OF OBESITY Manpreet Randhawa, Tom Huff, Julio C. Valencia, Zobair Younossi, Vikas Chandhoke, Vincent J. Hearing, Ancha Baranova

  2. Why obesity is so dangerous ? whyfiles.org/276metabolic_syndrome/

  3. METABOLIC SYNDROME Common complications : Cardiovascular diseases Diabetes type II Non-alcoholic fatty liver disease (NAFLD) Non-alcoholic steatohepatitis (NASH)

  4. Prevalence of the metabolic syndrome increases with age National Health and Nutrition Examination Survey III, 1988-1994(8814 US adults)

  5. Prevalence of metabolic syndrome increases with obesity Males , blacks;    , Hispanics;    , whites. Females

  6. U.S. INCIDENCE OF DIABETES (BOTH TYPES): CDC graph

  7. Cost burden of obesity (U.S. only) Direct cost only; 17% of total direct cost of heart disease, independent of stroke Direct and indirect costs Direct and indirect costs Direct cost only; 17% of total direct cost of hypertension

  8. Health-Care Costs for Obesity Top Those Related to Smoking There has definitely been a feeling that smoking, drinking and substance abuse are bigger problems than obesity. This isn't the case. Obesity is associated with an average increase in hospital and outpatient spending of $395 a year

  9. Prevalence of metabolic syndrome increases with obesity Males , blacks;    , Hispanics;    , whites. Glass half full or half empty? Some obese people stay healthy despite very high BMI (even within bariatric cohort) WHY? Females

  10. Non-Alcoholic Liver Disease as a modelfor the study of the secondary complications of obesity Liver transplantation  Fibrosis increased risk of hepatocellular carcinoma From: Ariel E. Feldstein and Marsha H. Kay, ACG website NAFLD affects up to 20 % of adults and nearly 5 % of children. NASH 2-5 % of adult Americans; up to 20 % of obese subjects. The majority of individuals with NAFLD have no symptoms and a normal examination Can we treat NAFLD ? Not really. Just try to lose weight….

  11. For these who thinks that fat in the liver is microscopic change

  12. IMPORTANT QUESTION: WHY SOME PATIENTS WITH VERY HIGH BMI (>45) STAY FREE OF LIVER DISEASE? ARE SOME PROTECTIVE FACTORS OR PREDISPOSING FACTORS INVOLVED? ARE THESE FACTORS PRESENT IN THE LIVER OR IN THE FAT?

  13. Obese Patients with NASH vs Obese patients without liver pathology Results of the Liver biopsy profiling (5K chip) Results of the visceral adipose profiling (40K chip) > 2.0 in the liver (NASH vs OC) = pro-NASH genes in the liver < 0.5 in the liver (NASH vs OC) = hepatoprotective genes in the liver > 2.0 in the adipose (NASH vs OC) = pro-NASH genes in the fat < 0.5 in the adipose (NASH vs OC) = hepatoprotective genes in the fat Dataset was downsized

  14. Genes that are regulated by TGF-β signal in adipose are important for the development of the primary phenotype of the morbid obesity TNF-α and IL6 regulated genes expressed in adipose play a prominent role in the development of NASH

  15. Major finding: Adipose of the NASH patients overexpresses a number of genes encodingsecreted, mostly pro-inflammatory molecules.

  16. IL-6 IL-8 Visfatin, Vaspin, Apelin, PAI-1, MCP1, other pro-inflammatory molecules Other cells embedded in adipose, including macrophages NAFLD and NASH develop under the influence of the adipokines synthetized in the visceral adipose

  17. ANOTHER study:Profiling of adiponectin, resistin, visfatin, apelin, TNF-alpha, IL-6, IL-8, IL1, IL1R, sIL-6in the serum of patients with and without NAFLD • 100 samples collected and profiled; • Correlation analysis with seven clinical parameters is completed;

  18. A. Visfatin B. B. TNF-α TNF-α 1000 1000 * 100 100 Mean (pg/ml) Mean (pg/ml) 10 10 1 Controls I (N=38) Controls II (N=12) NAFLD (N=45) SS (N=19) NASH (N=26) Controls I (N=38) Controls II (N=12) NAFLD (N=45) SS (N=19) NASH (N=26) TNF-α, pg/ml IL-8 IL-6 C. D. 100 100 1000 100 100 10 Mean (pg/ml) Mean (pg/ml) Mean (pg/ml) Lower than normal levels of TNF-α may prevent the onset of NAFLD in morbidly obese patients. 10 1 1 Controls I (N=38) Controls I (N=38) Controls II (N=12) Controls II (N=12) NAFLD (N=45) NAFLD (N=45) SS (N=19) SS (N=19) NASH (N=26) NASH (N=26) Controls I (N=38) Controls II (N=12) NAFLD (N=45) SS (N=19) NASH (N=26)

  19. General Theme: Visceral fat in some obese subjects remains inert; Something protects obese people with inert fat from metabolic syndrome

  20. Expression profiling in human OBESITY • Comparisons of the visceral fat samples; • >50 patients sampled during bariatric surgeries; • 9 lean peoples donating their kidney;

  21. Fat Tissue Stratagene human Ref. RNA Isolate total RNA Linearly Amplify RNA Linearly Amplify RNA Reverse Transcribe to cDNA, label with Cy5 Reverse Transcribe to cDNA, label with Cy3 Mix, Hybridize and Scan Fat Tissue Fat Tissue Fat Tissue Fat Tissue Stratagene human Ref. RNA Stratagene human Ref. RNA Stratagene human Ref. RNA Stratagene human Ref. RNA Isolate total RNA Isolate total RNA Isolate total RNA Isolate total RNA Linearly Amplify RNA Linearly Amplify RNA Linearly Amplify RNA Linearly Amplify RNA Linearly Amplify RNA Linearly Amplify RNA Linearly Amplify RNA Linearly Amplify RNA Reverse Transcribe to cDNA, label with Cy5 Reverse Transcribe to cDNA, label with Cy5 Reverse Transcribe to cDNA, label with Cy5 Reverse Transcribe to cDNA, label with Cy5 Reverse Transcribe to cDNA, label with Cy3 Reverse Transcribe to cDNA, label with Cy3 Reverse Transcribe to cDNA, label with Cy3 Reverse Transcribe to cDNA, label with Cy3 Mix, Hybridize and Scan Mix, Hybridize and Scan Mix, Hybridize and Scan Mix, Hybridize and Scan METHOD :

  22. Four comparisons were performed: • Morbidly obese (N=50) vs. Controls • Diabetic obese vs. normoglycemic obese • No significant genes found • Diabetic obese (N= 9) vs. Controls • NormoGlycemic Obese (N=22) vs. Controls

  23. All comparison were performed vs. Non-Obese Controls DMO = Obese with diabetes; MO =Obese without diabetes; NGO = NormoGlycemic Obese

  24. A LIST OF MELANOGENESIS RELATED GENES DIFFERENTIALLY EXPRESSED IN OBESE ADIPOSE • Genesfold difference Accession number TYRP1 2.66 AA668457 DCT 2.17 N27147 RAB27A 2.47 AI309109 RAB27B 2.6 R39044 MITF 1.5 N67822 SOX 1.36 AA976578 CHS1 1.22 N74383 Tyrosinase itself was not present on the chip

  25. Expression of TYR, TYRP1 and DCT in adipose tissue as revealed by Quantitative RealTime-PCR P < 0.007 P< 0.024 NS

  26. Fontana-Masson stain of human adipose tissue demonstrates melanin pigment (black staining) mainly in the periphery of the adipocytes. Cryoslicing of visceral adipose Melanin detection Fontana-Masson kit

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