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Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
Fat and Beyond: The Diverse Biology of PPAR gamma
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Fat and Beyond: The Diverse Biology of PPAR gamma

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  • Metabolism (carbohydrate & lipid ) for 2 point
  • . Influences intracellular trafficking and subcellular distribution. Along with the DBD, the LBD contributes to the dimerization interface of the receptor and in addition, binds coactivator and corepressor proteins. The LBD also contains the activation function 2 (AF-2) whose action is dependent on the presence of bound ligand.[15]
  • All these Ligands are activates PPAR in other tissues
  • Explain invitro and invivo in main article page 294 left sideForced expression of PPAR is sufficient to induce adipocytedifferentiatation in fibroblast and no factor has been discovered that promotes adipogenesis in absence of ppar
  • Results in expression of enzymes involved in mitochondrial respiratory chain to activate adaptive thermogenesis for 2 point
  • Transcript

    • 1. WELCOME
    • 2. Credit Seminar on SPEAKER P.RAMESH PH.D (ABC)
    • 3. PPARs (peroxisome proliferator-activated receptors ) are nuclear receptors & function as “Transcription factor” Essential roles in regulation of cellular differentiation, atherosclerosis & macrophage function 3 types have been identified: Alpha α, Gamma , and Delta  (Beta β) 3 α (alpha) - expressed in
    • 4. Cont… β/δ (beta/delta) - expressed in many tissues but markedly in brain, adipose tissue, and skin γ (gamma) - although transcribed by the same gene, this PPAR through alternative splicing is expressed in 3 isoforms: γ1 - expressed in virtually all tissues γ2 - expressed mainly in adipose tissue (30 A.As longer) 4
    • 5. PPAR is a ligand-activated transcriptional factor have a dominant role in development of adipose cells It is subfamily of structurally similar to nuclear receptor PPAR functions as an obligate heterodimer with RXRs High affinity binding to DNA by PPAR requires absolute dimerization with RXR (Tontonoz P, et al., 1994) Domains of PPAR proteins present nearly all nuclear hormone receptor Retinoid X Receptor 5
    • 6. Cont… C N PPAR has two N-terminal variants formed by alternative splicing (Adams M, et al., 1997)  PPAR 2 is expressed in more adipose selective manner N-terminal region influences the response to ligand 6 binding of LBD by phosphorylation at ser112 al., 1996) (Hu E, et
    • 7. N C DNA-binding domain (DBD): Highly conserved domain containing two zinc fingers which binds to specific sequences of DNA called hormone response elements (HRE) 7 C-terminal region is responsible for dimerization with RXR (Ren D, et al., & contains Transcriptional activation domain (AF2) 2002)
    • 8. Cont… C-terminal region also form ligand binding pocket, with many hydrophobic residuces occuring inside the pocket Crystal structure of PPAR LBD 8 (Gampe RT, et al., 2000)
    • 9. Cont…  PPAR activation induced by ligand dependent and independent mechanisms  Absence of ligand, corepressors bind to heterodimers & recruit Histone deacetylases to repress transcription  After ligand binding, increase PPAR affinity for number of co-activators  N-terminal regulatory domain: Contains the activation function 1 (AF-1) whose action is independent of the 9 presence of ligand (Tontonoz P, et al., 1994)
    • 10.  Co-activators: These are not themselves regulated at expression level CBP/p300 SRC family TRAP220 PGC-1α Co-repressors: SMART NCoR RIP140 10
    • 11. Cont… Biological Ligands: Polyunsaturated fatty acids Prostanoids (15-deoxy-12,14 prostaglandin-J2) Leukotriene LTB4 Oxidized fattyacids (9-HODE & 13-HODE) Lysophosphatidic acid Synthetic Ligands: Thiazolidinedion (TZD) Anti-Diabetic Drug Fibrates (Hyperlipidemia) 11 (Debevec D, et al., 2007)
    • 12. Adipocyte is central player in control of energy balance & whole body lipid homeostasis PPAR is dominant or “master” regulator of Adipogenesis It induces differentiation of pre-adipocytes into adipocytes & expressed in BAT and WAT (Sears I, et al., 1996) C/EBP-β/ bind to PPAR promoter & activates PPAR 12 Upon ligand activation, PPAR induces many target genes involved in Lipogenesis & Adipogenesis
    • 13. KLF5 CHOP KLF1 5 SREBP1 C KLF2 C/EBP PPAR KROX20 C/EBP C/EBP C/EBP GATA2 /3 Genes of Adipocyte differentiation Anti-adipogenic factors Activation Inhibition 13 (Evan D, et al., 2006)
    • 14. INSULIN IGF-1 WNT10b TGF SHH FGF BMPs SMO PTC Testosterone IRS -Catenin AR SMAD3 P ? SMAD3 + SHN2 SMAD1 P13K AKT/PKB C/EBP CREB FOXO1/A2 ? TCF/LEF GATA2/3 ? PPAR OTHERS 14 (Evan D, et al., 2006)
    • 15. Anti-Diabetic drugs Dietary fattyacids PPAR Intracellular fattyacids Prostaglandins PGJ2 Ap2 CBP RXR SRC LPL CD36 p300 RNA pol-II PEPCK Aquaporin7 GLUT4 Perilipin PGAR GlyK Fig: Role of PPAR pathway for Adipogenesis 15
    • 16. 16
    • 17. Triacylglycerols (Chylomicrons) Glucose (Liver) CD36 GLUT4 Liver Fattyacids Glucose Glycerol-3-P PEPCK LPL Aquaporin7 FattyacylcoA Perilipin Triacylglycerols HSL Glycerol Adipocyte Fattyacids 17
    • 18. Triacylglycerols (Chylomicrons) Glucose (Liver) LPL CD36 GLUT4 Liver Fattyacids Glucose Glycerol-3-P Aquaporin7 FattyacylcoA PEPCK Perilipin Triacylglycerols HSL Glycerol Adipocyte Fattyacids 18
    • 19. PPAR extensively studied in WAT differentiation & same receptor is also important in BAT development & function Thermogenic effect of PPAR in BAT is mediated by PGC1α, induced by cold exposure of animals (Sears I, et al., 1996) PGC-1α regulates activation of PPAR on thermogenesis & fattyacid oxidation by interacting with PPAR/RXR Stimulation of uncoupling protein (UCP-1), responsible 19 for uncoupling β-oxidation PPAR Coactivator-1
    • 20. Cont… Phosphorylated PGC-1α is recruited PPAR binding site on UCP-1 promoter PGC-1α is stabilized & activated by p38 MAP kinases PGC-1α binds to PPAR by its LBD in a ligand independent manner LXXLL motif containing co-activator binds to PPAR Insulin/akt pathway shutdown hepatic gluconeogenesis, phosphorylation of PGC-1 (McInerney E, et al., 1998) 20
    • 21. G protein ATP cAMP MAP kinas e PGC1 P PPAR UCP-1 (Sears I, et al., 1996)
    • 22. Cont… 22 Fig: Thermogenesis by UCP-1 in BAT
    • 23. Insulin Resistance: is a condition in which body cells become less sensitive to the glucose-lowering effects of the hormone insulin Type2 Diabetes mellitus: Pancreas secrete normal or even greater than normal amount of insulin Hallmark of type2 Diabetes is Insulin Resistance In type2 Diabetes, plasma levels of FFAs & Glucose are 23 increased
    • 24. In T2DM inappropriate deposition of lipids in liver & skeletal muscle Thiazolidinedione (TZD), Rosiglitazone & Pioglitazone are used for treatment of type2 Diabetes (Haris P, et al., 1994) Activation of PPAR target gene expression enhance to store dietary fattyacids Target genes contributing to this include AP2, LPL, CD36, PEPCK & Aquaporin 7 24 (Kishida K, et al., 2001)
    • 25. Cont… Adipose tissue is primary target for effects of TZD It also promotes many signaling molecules called Adipokines from adipocytes Adiponectin Resistin TNFα INFLAMMATORY RESPONSE MCP-1 IL-6, IL-1β (Bouskila M, et al., 2005) 25
    • 26. Ligand activation (TZD) of PPAR in adipocytes is associated with decreased production of TNFα, Resistin & MCP-1 Increase of Adiponectin gene Decreased Insulin Resistance Suppression of Hepatic glucose uptake & stimulates muscle glucose uptake 26
    • 27. ADIPONECTINS:  It is a protein hormone abundantly expressed in adipocytes  Adiponectin affects:  Decreased gluconeogenesis  Increased glucose uptake  β-oxidation  Triglyceride clearance  Protection from endothelial dysfunction  insulin sensitivity 27
    • 28. TNF-α: Cont… It is an inflammatory cytokine released in obese & insulin resistance Also propagates atherosclerotic lesion formation It also promotes apoptosis in endothelial cells by dephosphorylating protein kinase B or Akt & contribute endothelial injury 28
    • 29. Cont… RESISTIN:  It is recently discovered fat-specific hormone, directly induces insulin resistance in muscle & liver  Neutralization of resistin by specific antibodies results in decreased blood glucose level  It also express cell adhesion molecule (VCAM-1), chemokine MCP-1(Atherosclerotic lesion formation) with insulin resistance patients 29
    • 30. Insulin Muscle Liver Adipocyte Hypertrophy ? RESISTIN Diet induced Obesity Adipocyte 30 (Olavi U, et al., 2002)
    • 31. Adipokines & Inflammation:  Increased in adipose tissue (WAT) with obesity during inflammation (TNF-α, IL-6,IL-18, MIF, CRP & PAI-1)  Circulatory inflammatory markers are raised in obese  IL-6 released from adipose tissue stimulates hepatic synthesis of CRP in obese  Similary IL-18 is acivated by TNF-α 31 (Trayhurn P, et al., 2005)
    • 32. Cont…  Why Obese should be accompanied by Inflammation???  It is mainly due to HYPOXIA  Adipose tissue (WAT) mass is very large in Obese & Type-II diabetes are linked to inflammation (Sears I, et al., 1996) 32
    • 33. TZD effects on Skeletal Muscle and Liver: Skeletal Muscle is largest glucose utilizing organ, ability of TZD is to improve whole body insulin resistance PPARγ expression is very low in Skeletal muscle compare to fat Effect of PPARγ ligands on skeletal muscle for glucose uptake are likely to be indirect Direct of effect of PPARγ activation in muscle is still 33 unclear (Castrillo A, et al., 2004)
    • 34. Cont… In liver also expression of PPARγ is very low, activation of PPARγ signaling promotes lipid accumulation (Hepatic Steatosis) in rodents But does not appear in human hepatic steatosis TZD is beneficial in treating nonalcoholic fatty liver disease in humans (Castrillo A, et al., 2004) 34
    • 35. PPARγ is induced differentiation of monocytes into macrophages & highly expressed in Macrophages It also differentiates of monocytes into dendritic cells Oxidized ligands (9-HODE & 13-HODE) & lipoproteins responsible for PPARγ signaling in myeloid cells Upon ligand activation, it promotes expression of genes CD36, LXR, Arg-1& IL-10 (Sears I, et al., 1996) 35
    • 36. 36
    • 37.  PPARγ is a lipid-activated member of the nuclear receptor superfamily of transcription factors  Biological receptor for the TZD class of antidiabetic drugs  Master transcriptional regulator of adipocyte differentiation & controls expression of a genes involved in lipid metabolism  PPARγ action in myeloid cells, such as macrophages and 37 DCs, has been linked to the modulation of immune and
    • 38. 38

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