Fisiología Integral de la Obesidad: Obesidad y Diabetes

1. Fisiología Integral de la Obesidad: Obesidad y Diabetes Dario C. Ramirez Laboratorio de Medicina Experimental y Terapéuticas Cátedra de Genética Molecular Facebook: Dario C Ramirez E-mail: ramirezlabimibiosl@ymail.com

2. Obesidad: definición, etiología y prevalencia

3. MEDIDAS ANTROPOMÉTRICAS • Peso del cuerpo (kg) • Altura (m) (Las medidas fueron tomadas mientras los sujetos estaban descalzos y con ropas livianas) • El índice de masa corporal (BMI) fue calculado como: IMC =peso del cuerpo[ = ] kg/m2 (altura)2 • La circunferencia de cintura (cm) se mide a la altura del ombligo

4. Grados de Obesidad según IMC ( Kg/m2 )

7. Modelo causal de la obesidad

9. 2008 1994 2000 2008 1994 2000 No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0% No Data <14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0% Age-adjusted Percentage of U.S. Adults Who Were Obese or Who Had Diagnosed Diabetes Obesity (BMI ≥30 kg/m2) Diabetes CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics

10. La obesidad crece en Latinoamérica. Entre los años 1995 y 2012 la población obesa mayor a 15 años creció un 99%, reflejando que un 26,54% de los latinoamericanos se pueden catalogar como  obesos. - See more at: http://blog.euromonitor.com/2013/06/obesidad-en-latinoam%C3%A9rica-factores-detr%C3%A1s-del-incremento.html#sthash.FLUY9bDH.dpuf "La prevalencia de diabetes en la población argentina es de 8.5%“ – ADA 2010

11. Complicaciones metabólicas de la obesidad

12. PERFILES LIPÍDICOS Perfiles lipídicos alterados OBESIDAD DMT2 Con o sin tolerancia a la glucosa Obesos y no obesos • Anormalidades lipídicas: • TG aumentados • LDL aumentadas • HDL disminuidas

13. Diabetes Mellitus • Signos y síntomas • Poliuria • Polidipsia • Polifagia • Infecciones recurrentes (cutáneas, urinarias, etc.) • Pérdida de peso o aumento de peso • Prurito • Sequedad de la boca • Alteración visual • Fatiga Gentileza Dras: Ojeda y Sweret (Laboratorio de Diabetes UNSL)

14. Examen de glucosa

15. Clasificación de la Diabetes

16. Síndrome metabólico

18. La inflamación del TA es la causante de las metabolopatías asociadas a la obesidad

19. 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

20. WAT BAT

21. 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(+)

22. Differences in the fate of fatty acids between brown and white fat cells Lipolysis FA esterification FA esterification b oxidation White adipocyte Brown adipocyte Glycerol Glycerol FA FA Glycerol FA Glycerol Lipolysis Triglycerides Triglycerides FA FA FA FA FA FA Glycerol-3P Glycerol-3P Glucose, amino acids, lactate, pyruvate Glycerol, glucose

23. Adipose tissue development : beyond adipocyte differentiation Mature adipocytes Preadipocytes Endothelial cells Mature adipocytes ADIPOCYTE HYPERTROPHY & HYPERPLASIA ANGIOGENESIS INFLAMMATION Macrophages Preadipocytes

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

25. PKA Adrenergic control of metabolism in brown fat cells 1, 2, 3 A C Plasma membrane Gs T HERMOGENESIS Mitochondrial biogenesis (PGC1) UCP1 transcription cAMP UCP1 activation Lipolysis (FA) b oxidation

26. White adipose tissue as an endocrine organ

27. Crosstalk between the cells ADIPOCYTE Leptin  HYPERTROPHIED ADIPOCYTE  NEFAs Cytokines  Hypertrophy of adipocytes & triglyceride overload Adiponectin NEFA others MCP-1 MIP-1a others TNF-a MCP-1 IL-1b others preadipocyte TNF-a others Macrophage TNF-a MIP-1a MCP-1 others Activation and infiltration of macrophages

28. Mecanismo central de regulación del peso corporal

29. b oxidation FA, Other metabolites, Adipokines, … Glycerol Lipolysis FA FA Triglycerides FA FA esterification Glycerol-3P TNFa, Cytokines, Chemiokines, …

30. El rol de los macrófagos en la inflamación del TA en obesidad

31. Macrophages cause fat tissue inflammation Inflamed fat tissue Fat tissue Adp Lep Lep Adp Furukawa, S. et al. 2004. J. Clin. Invest. 114: 1752-1761 Minamino et al. 2009. Nat. Med. 15:1082-1087 Lumeng, C.N. et al. 2007. J. Clin. Invest. 117: 175-184

32. Modified from: Nature Clin. Pract. Endocrinol. Metab. (2008) 4, 619-626 Lumbeng, C.N.; et al. 2007. J. Clin. Invest. 117:175-184.

33. Caracteristicas de pacientes obesos insulin sensibles (IS) e insulino resistentes (IR) Kloting, N. et al. Am J Physiol Endocrinol Metab 299: E506-E515 2010

34. FIG. 2 Diabetes. 60(12):3159-3168, December 2011. FIG. 2 . Body weight change and adiposity in HFD-fed 4-1BB-deficient mice. WT and 4-1BB-deficient mice were fed an HFD for 9 weeks. A: Expression of 4-1BB mRNA in epididymal adipose tissue, liver, and skeletal muscle. Body weight changes and gross morphology of mice (B), energy intake (C), and adipose tissue weight (Ep, epididymal; Re, retroperitoneal; Me, mesenteric; and Sc, subcutaneous) of WT (n = 8) and 4-1BB-deficient mice (n = 8) fed an RD or HFD, and gross morphology of adipose tissues (D). Results are means +/- SEM. *P P P E: Histological analysis of epididymal adipose tissue and size distribution of adipocytes from WT and 4-1BB-deficient mice fed an HFD. Sections were stained with hematoxylin-eosin. Hypertrophied adipocytes are indicated by asterisks. Original magnification is x200 (scale bar = 50 [mu]m). The sizes of adipocytes in randomly chosen fields were measured with a microscope (magnification x200) and calculated using Axiovision AC software. #P < 0.005 compared with WT mice fed an HFD. WAT, white adipose tissue. (A high-quality color representation of this figure is available in the online issue.) 4

35. Aspectos bioquímicos de la obesidad y sus complicaciones

37. Role of adipokines and cytokines in obesity complications Subcutaneous adipose tissue Visceral adipose tissue macrophages IL-6 TNF-a Secretions : Leptin Adiponectin RBP4 TNF-a, IL-6… Skeletal muscle Liver utilisation glucose Other target tissues Vessels atherosclerosis, hypertension Non alcoholic CRP steatohepatitis PAI1 Glucose intolerance Insulin resistance Obesity complications

38. Coordination of the regulation of fat deposition and fat mobilization in white adipose tissue Fed Fasting LPL Triglycerides Fatty acids + Gut Esterification + Triglycerides - + Catecholamines Glycerol 3-phophate ANP, BNP Lipases Glucose Fatty Acids + Glycerol To liver, muscle + Glut4 To liver Pancreas Insulin

39. Dislipemia en el Síndrome Metabólico ASP ApoB VLDL TG ApoC II-III- E Ac. Grasos Adipocito Hígado Riñon ApoA1 VLDL CE HDL CE TG CETP CETP IR actividad de la lipoproteinlipasa IDL TG CETP CE TG LDL Lipasa hepatica LPL LDL pequeña Grundy MS et al. Am J Cardiol 1998; 81: 18

41. Role of fatty acids in obesity complications Subcutaneous adipose tissue Visceral adipose tissue Vessels Thrombosis Heart Myocardial performance Portal and visceral FA Abdominal FA FA hepatic flux Skeletal muscle Liver Hepatic glucose production Non alcoholic steatohepatitis Glucose utlization Pancreas Increased synthesis of TG-rich VLDL Hyperinsulinemia Glucose intolerance Insulin resistance Hyperlipidemia Obesity complications

42. Bases moleculares de la resistencia a la insulina en obesidad

43. 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.

44. Deleterious effects of an excess of nonesterified fatty acids SNS activity Triglycerides Myocardial performance Increased lipolysis Thrombosis Antilipolytic effect HDL-C NEFA VLDL secretion Insulin resistance LDL particle size Glucose utilisation Glucose production Glucose intolerance Hyperinsulinemia Hypertension

45. Insulin’s command: “utilize glucose now, build proteins and store energy for the future” De Luca & Olefsky, FEBS Lett. 2008,582(1): 97–105

46. Journal of Clinical Investigation. 116(7):1793-1801, July 2006. 2

47. Nature. 444(7121):860-867, December 14, 2006. 7 Figure 6 Therapeutic targets at the interface between metabolic and inflammatory pathways. The pathways are divided into peptide- and lipid-mediated targets for practical purposes and do not represent an exhaustive list. Treating several loci involved in the disease process by targeting organelles such the ER and mitochondria represents a new approach to treating metabolic diseases.

48. Nature. 444(7121):860-867, December 14, 2006. Figure 5 Molecular pathways integrating stress and inflammatory responses with insulin action. IRS-1 and 2 are crucial signalling molecules in insulin action. Activation of JNK by cytokine signalling, lipid products, ROS or through IRE1 during ER stress leads to serine phosphorylation of IRS-1 and 2, and consequently inhibits insulin signalling. Similar signals, including PERK, also activate IKK and inhibition of insulin action through a series of transcriptional events mediated by NF-[kappa]B. JNK also regulates transcription through AP-1. Lipid-activated transcriptional events are mediated by nuclear hormone receptors PPAR and LXR. The biological activities of lipids are regulated by FABPs that function as chaperones. Mitochondria and the ER can both contribute to ROS production. ATF6 and XBP1 are critical regulators of ER function and its adaptive responses. 6

49. Genetics of obesity and its complications

50. Niveles de la regulación de la expresión génica Chromosome DNA unpackingOther changes to DNA GENE TRANSCRIPTION GENE Exon RNA transcript Intron Addition of cap and tail Splicing Tail Cap mRNA in nucleus NUCLEUS Flowthroughnuclear envelope mRNA in cytoplasm CYTOPLASM Breakdown of mRNA Translation Broken-down mRNA Polypeptide Cleavage/modification/activation ACTIVE PROTEIN Breakdownof protein Broken-down protein