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Fisiología Integral de la Obesidad: Obesidad y Diabetes Dario C. Ramirez Laboratorio de Medicina Experimental y Terapéuticas Cátedra de Genética Molecular.

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Presentación del tema: "Fisiología Integral de la Obesidad: Obesidad y Diabetes Dario C. Ramirez Laboratorio de Medicina Experimental y Terapéuticas Cátedra de Genética Molecular."— Transcripción de la presentación:

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

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/m 2 ( altura) 2 La circunferencia de cintura (cm) se mide a la altura del ombligo

4 Grados de Obesidad según IMC ( Kg/m 2 ) IMC (20 – 25 normal) GRADO DE SOBREPESO TIPO DE OBESIDAD 25 – 30ILeve 30 – 35IIModerada 35 – 40IIIGrave 40 – 50IVMórbida > 50VSuper-obesidad

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7 Modelo causal de la obesidad

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9 2008 Age-adjusted Percentage of U.S. Adults Who Were Obese or Who Had Diagnosed Diabetes Obesity (BMI 30 kg/m 2 ) Diabetes No Data 26.0% No Data 9.0% CDCs Division of Diabetes Translation. National Diabetes Surveillance System available at 2008

10 "La prevalencia de diabetes en la población argentina es de 8.5% – ADA 2010 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: latinoam%C3%A9rica-factores-detr%C3%A1s-del-incremento.html#sthash.FLUY9bDH.dpufhttp://blog.euromonitor.com/2013/06/obesidad-en- latinoam%C3%A9rica-factores-detr%C3%A1s-del-incremento.html#sthash.FLUY9bDH.dpuf

11 Complicaciones metabólicas de la obesidad

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

13 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 Diabetes Mellitus Gentileza Dras: Ojeda y Sweret (Laboratorio de Diabetes UNSL)

14 Examen de glucosa

15 Clasificación de la Diabetes

16 Síndrome metabólico

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

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

20 WAT BAT

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

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

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

24 proliferation fat cell-specific gene expression differentiation Transcriptional control of adipocyte differentiation Wnt signaling GATA 2 & 3 SREBP1c / ADD1 C/EBP / PPAR C/EBP RXR PPAR J. Lipid Res., 2002, 43,

25 1, 2, 3 cAMPPKA ACAC Gs Plasma membrane Mitochondrial biogenesis (PGC1) UCP1 transcription Lipolysis (FA) UCP1 activation oxidation THERMOGENESISTHERMOGENESIS Adrenergic control of metabolism in brown fat cells

26 White adipose tissue as an endocrine organ

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

28 Mecanismo central de regulación del peso corporal

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

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

31 Macrophages cause fat tissue inflammation Furukawa, S. et al J. Clin. Invest. 114: Minamino et al Nat. Med. 15: Lumeng, C.N. et al J. Clin. Invest. 117: Fat tissue Adp Lep Adp Inflamed fat tissue

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

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

34 4 FIG. 2 Diabetes. 60(12): , December 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 < 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.)

35 Aspectos bioquímicos de la obesidad y sus complicaciones

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37 Role of adipokines and cytokines in obesity complications IL-6 TNF- Liver utilisation glucose Skeletal muscle macrophages Other target tissues Vessels atherosclerosis, hypertension Secretions : Leptin Adiponectin RBP4 TNF-, IL-6… Non alcoholicCRP steatohepatitisPAI1 Visceral adipose tissue Subcutaneous adipose tissue Obesity complications Glucose intolerance Insulin resistance

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

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

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

42 Bases moleculares de la resistencia a la insulina en obesidad

43 Alternate fuel source for brain and other organs Liver Ketone bodies and CO 2 VLDL Adipose tissue TG LPL Lipases Chylomicrons (lymphatic circulation) Intestinal absorption Muscle, myocardium, kidney cortex, etc. LPL TG CO 2 FA TG NEFA Overview of fatty acid metabolism Essays Biochem. 2006;42:

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

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

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

47 7 Nature. 444(7121): , December 14, 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 6 Nature. 444(7121): , December 14, 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.

49 Genetics of obesity and its complications

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

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53 Polygenic obesity Challenge Discover pertinent genes, gene combinations and interactions Rare monogenic mutation LEPR, POMC, PCSK1 SIM1, LEP, others Increased energy INS-VNTR MC4R HNF1A LPLHSL PPARG mtDNA ADRB3 GYS UCP1 Decreased energy expenditure GNB3 APOE AGT KCNJ11 MC4R

54 Identifying Disease Genes Family Based Linkage Studies Population Based Association Studies Members of a family affected by the Same disease share Identical disease genes Distribution of disease alleles is Different between Cases and Controls

55 Genetics of human obesity Dissection and strategy Environment Genes Monogenic High penetrance Monogenic Low penetrance Variable expression Polygenic Rare cases Syndromes Population study Genetic epidemiology Tissue investigation in clinical trials omic studies Example: Adipose tissue analysis

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57 Candidate genes in obese populations Food intake-central Monoamines, Peptides&receptors : CART, DRD2, NPY, NPYR, MC3R, POMC, HT2A, AGRP, MC3R, MC4R Food intake-peripheral Pancreatic peptides; Isl1, CCK receptors A&B, GLP1-R Thermogenesis AR1, 2, 3, AR, CAPN10 UCP1, 2, 3 And others.. FAT and glucose metabolism leptin, leptinR,insulin, InsR, SUR, PTP1b, IRS1, Isl1, GCK LPL, HSL, GRL, DGAT, CPT-1 apoA4, B, E, CD36, FABP2, LDLR, LIPE, GRL, TNF, TNF-R, adiponectin Master genes ? PPAR, CDX3, SREBP1 49 Negative associations 30 Positive associations Morbid obesity Life span Weight gain Obesity onset Fat mass Glucid values Lipid values Food intake Physical activity

58 Fisiología integral de la obesidad y sus complicaciones

59 SNP Databases dbSNP Human Genome Variation Database (HGVbase) TSC: The SNP Consortium

60 Nuevos enfoques

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62 NUTRITION (Imbalance between energy intake and expenditure ) GENOME (SNPs in the MPO promoter) ENVIRONMENT (endotoxin inhalation) OBESITY Adipocyte hypertrophy and hyperplasia Hypoxia Recruitment of Type M1 macrophages (M ) M synthesize and release MPO and IR- inducing cytokines Adipocytes take up MPO FAT TISSUE DYSFUNCTION homing of neutrophils in the lung LUNG INFLAMMATION (Synthesis of IR-inducing mediators) Circulating pro-inflammatory and IR- inducing cytokines INSULIN RESISTANCE Type 2 diabetes Nutritional, genetic and environmental factors contribute to the incidence of type 2 diabetes in obese patients


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