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Adipocytes and CVD

Adipocytes and CVD. Ms. Leonardo Roever. (n=3,928). (n=1,808). (n= 685). (n=1,430). Prevalence of CHD, MI, and Stroke in Relation to the Presence of Metabolic Syndrome. All Subjects NGT IFG/IGT Type 2 Diabetes. WITH Metabolic Syndrome. 30. 25. 20. 15. 10. 5. Prevalence. 0. 30.

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Adipocytes and CVD

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  1. Adipocytes and CVD Ms. Leonardo Roever

  2. (n=3,928) (n=1,808) (n= 685) (n=1,430) Prevalence of CHD, MI, and Stroke in Relation to the Presence of Metabolic Syndrome All Subjects NGT IFG/IGT Type 2 Diabetes WITH Metabolic Syndrome 30 25 20 15 10 5 Prevalence 0 30 CHD Previous MI Previous Stroke 25 Without Metabolic Syndrome 20 15 10 5 0 CHD Previous MI Previous Stroke Isomaa et al. 2001. Diabetes Care. 24:683-689.

  3. Fat mass, adipose tissue and energy stores Liver triglycerides = 450 kcal Muscle triglycerides =3000 kcal Liver glycogen = 400 kcal Muscle glycogen =2500 kcal Adipose tissue triglycerides = 120,000 kcal Data for a 70 kg lean subject. Subject with morbid obesity : x 8 TG

  4. Anatomical distribution of adipose tissue • Subcutaneous adipose tissue : • - abdominal • - femoral • Intraabdominal adipose tissue : • - visceral (mesenteric and omental) • retroperitoneal (perirenal and • perigonadic) • Other depots : • - intra and intermuscular • - perivascular • - epicardiac Different physiological and pathogenic roles of the fat depots

  5. Gender Differences in Adipose Tissue Distribution Female Male Original Image SCAT Subcutaneous Adipose Tissue HIGHLIGHTED WHITE VAT Visceral Adipose Tissue HIGHLIGHTED WHITE J. Magn. Reson. Imaging Vol.21, 4 Pages: 455-462

  6. Secretory Products of Adipose Tissue Bone Morphogenic Protein TNF-α Interleukins TGF β FGF EGF IGF-1 IGFBP Fatty Acids Lactate Adenosine Prostaglandins Glutamine Resistin  Adipose Tissue Adiponectin      Unknown Factors   Estrogen Ang II PAI-1 Angiotensinogen Leptin Adapted from: Roth, J, et al, Obesity Research, Vol 12, supplement Nov 2004:88S-101S

  7. Obese with full metabolic dysfunction Necrotic adipocyte Crown-like structure Proinflammatory cytokines Leptin CCL2 TNF CXCL5 IL-6 IL-18 Obesity + inflammatory infiltration of fat tissue Lean with normal metabolic function …… Adipocyte …… CD4+T cell Macrophage (M2) Modified from Ouchi N et al., Nat Rev Immunol 2011

  8. Anatomy and nomenclature of commonly studied perivascular adipose depots. Fitzgibbons T P , and Czech M P J Am Heart Assoc 2014;3:e000582

  9. Heterogeneous distribution of adipose tissue and risks of metabolic and cardiovascular complications The apple The pear Visceral vs. subcutaneous obesity Gender differences Differences in risk for complications Dyslipidemia, type 2 diabetes, hypertension, coronary heart disease, … Nature. 2006 444:881-7

  10. Signaling pathways that mediate the paracrine effects of PVAT. Adiponectin (ADIPOQ) has been shown to mediate many of the beneficial effects of PVAT. ADIPOQ is more highly expressed in lean conditions (top) than in obese conditions (bottom). Fitzgibbons T P , and Czech M P J Am Heart Assoc 2014;3:e000582

  11. Medical Complications of Obesity Idiopathic intracranial hypertension Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome Stroke Cataracts Nonalcoholic fatty liver disease steatosis steatohepatitis cirrhosis Coronary heart disease Diabetes Dyslipidemia Hypertension Gall bladder disease Severe pancreatitis Gynecologic abnormalities abnormal menses infertility polycystic ovarian syndrome Cancer breast, uterus, cervix colon, esophagus, pancreas kidney, prostate Osteoarthritis Phlebitis venous stasis Skin Gout

  12. White adipose tissue For letter symbols, see slide 36

  13. WAT BAT For letter symbols, see slide 36

  14. Multilocular adipocyte Lipid storage and mobilization (++) Mitochondria (+++) Fatty acid oxidation (+++) Respiratory chain (+++) UCP1 (+++) PGC-1a(+++) Brown adipocyte Characteristics of brown and white adipocytes White adipocyte Unilocular adipocyte ( 200µm) Lipid storage and mobilization (+++) Mitochondria (+) Fatty acid oxidation (+) Respiratory chain (+) UCP1 (0) PGC-1a(+)

  15. SREBP1c / ADD1 RXRa PPARb PPARg C/EBPb/d C/EBPa Wnt signaling GATA 2 & 3 Transcriptional control of adipocyte differentiation proliferation differentiation fat cell-specific gene expression J. Lipid Res., 2002, 43, 835-860

  16. Thermogenesis Fat storage & mobilization Endocrine organ PGC-1a PRDM16 Biochem J. 2006 398:153-68 Genes Dev, 2000, 14, 1293-1307

  17. Overview of fatty acid metabolism Alternate fuel source for brain and other organs Liver NEFA TG Ketone bodies and CO2 Adipose tissue VLDL TG LPL Lipases NEFA Chylomicrons (lymphatic circulation) LPL TG FA Muscle, myocardium, kidney cortex, etc. Intestinal absorption CO2 Essays Biochem. 2006;42:89-103.

  18. IR Glucose VLDL CL LPL ASP CD36 FAT GLUT4 NH2 IRS GLUT4 PDE 3B PI3-K COOH Glucose 6-P PKB Pyruvate Fatty acids Acetyl-CoA Glycerol 3-P Fatty acids DGAT Fatty acid and glucose metabolism in white adipocytes 1- 2- 3- AR 2-AR NH2 AC Gs Gi COOH ATP cAMP 5' AMP PKA ALBP ATGL HSL HSL P Perilipins Fatty acids Triglycerides

  19. Lipolysis in human white adipocytes ATGL FFA glycerol Natriuretic peptide receptor A ? Aquaporin 7 Insulin receptor ALBP-FA GC MGL AMPK cGMP IRS triglycerides HSL HSL PKG PI3-K ? PDE-3B PKB Perilipin PKA cAMP b1/2-AR, Others ? Gs Gi AC a2-AR, HM74A, A1 receptor, EP3 receptor, Y1 receptor Pharmacol. Res. 2006 53:482-91

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