Fisiología Integral de la Obesidad: Obesidad y

Diabetes

Dario C. RamirezLaboratorio de Medicina Experimental y Terapéuticas

Cátedra de Genética Molecular

Facebook: Dario C RamirezE-mail: ramirezlabimibiosl@ymail.com

Obesidad: definición, etiología y prevalencia

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

Grados de Obesidad según IMC ( Kg/m2 )

IMC

(20 – 25 normal)

GRADO DE SOBREPESO

TIPO DE OBESIDAD

25 – 30 I Leve

30 – 35 II Moderada

35 – 40 III Grave

40 – 50 IV Mórbida

> 50 V Super-obesidad

Modelo causal de la obesidad

2008

Age-adjusted Percentage of U.S. Adults Who Were Obese or Who Had Diagnosed Diabetes

Obesity (BMI ≥30 kg/m2)

Diabetes

1994

1994

2000

2000

No Data <14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0%

No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0%

CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics

2008

"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: http://blog.euromonitor.com/2013/06/obesidad-en-latinoam%C3%A9rica-factores-detr%C3%A1s-del-incremento.html#sthash.FLUY9bDH.dpuf

Complicaciones metabólicas de la obesidad

PERFILES LIPÍDICOS

Perfiles lipídicos

alterados

DMT2 OBESIDAD

Obesos y no obesosCon o sin tolerancia a la

glucosa

Anormalidades lipídicas:

TG aumentados

LDL aumentadas

HDL disminuidas

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)

Examen de glucosa

Clasificación de la Diabetes

Síndrome metabólico

La inflamación del TA es la causante de las

metabolopatías asociadas a la obesidad

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 tissueAnatomical distribution of adipose tissue

Different physiological and pathogenic roles of the fat depots

WAT

BAT

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 adipocyteMultilocular adipocyteLipid storage and mobilization (++)Mitochondria (+++)Fatty acid oxidation (+++)Respiratory chain (+++)UCP1 (+++)

PGC-1 (+++)

Differences in the fate of fatty acids between brown and

white fat cells

FAFA

Glycerol

Lipolysis

FA esterification

FA

Glycerol

TriglyceridesFA

Glycerol-3P

FA

Glycerol

FA

oxidation

FA

Glycerol

Triglycerides

White adipocyte Brown adipocyte

Glycerol-3P

Glucose, amino acids, lactate, pyruvate

Lipolysis

FA esterification

FA

Glycerol, glucose

FA

ADIPOCYTE HYPERTROPHY

& HYPERPLASIA

ADIPOCYTE HYPERTROPHY

& HYPERPLASIA

ANGIOGENESISANGIOGENESIS

INFLAMMATIONINFLAMMATIONMacrophages

Mature adipocytes

Preadipocytes

Endothelial cells

Mature adipocytes

Preadipocytes

Adipose tissue development : beyond adipocyte differentiation

proliferation

fat cell-specific gene expression

differentiation

Transcriptional control of adipocyte differentiation

Wnt signalingGATA 2 & 3

SREBP1c / ADD1

C/EBP /

PPAR

C/EBP

RXRPPAR

J. Lipid Res., 2002, 43, 835-860

1, 2, 3

cAMP PKA

AC

Gs

Plasma membrane

Mitochondrial biogenesis (PGC1)

UCP1 transcription

Lipolysis (FA)

UCP1 activation

oxidation

THERMOGENESIS

Adrenergic control of metabolism in brown fat cells

White adipose tissue as an endocrine organ

Hypertrophy of adipocytes& triglyceride overload

Activation andinfiltration of

macrophages

Adiponectin

TNF-MIP-1MCP-1others

MCP-1MIP-1others

TNF-others

TNF-MCP-1IL-1others

NEFAothers

HYPERTROPHIEDADIPOCYTE

ADIPOCYTE

MacrophageNEFAs

Leptin

Cytokines

preadipocyte

Crosstalk between the cells

Mecanismo central de regulación del peso corporal

FA,Other metabolites,Adipokines,…

TNF,Cytokines,Chemiokines,…

FA

Glycerol-3P

FA

Glycerol

FA

oxidation

Lipolysis

FA esterification

Triglycerides

El rol de los macrófagos en la

inflamación del TA en obesidad

Macrophages cause fat tissue inflammation

Furukawa, S. et al. 2004. J. Clin. Invest. 114: 1752-1761Minamino et al. 2009. Nat. Med. 15:1082-1087Lumeng, C.N. et al. 2007. J. Clin. Invest. 117: 175-184

Fat tissue

Adp

Lep

Lep

AdpInflamed fat tissue

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

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Caracteristicas de pacientes obesos

insulin sensibles (IS) e insulino resistentes

(IR)

4

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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.)

Aspectos bioquímicos de la obesidad y sus

complicaciones

Role of adipokines and cytokines in obesity complications

IL-6TNF-

Liver

utilisation glucose

Skeletalmuscle

macrophages

Other target tissues Vessels

atherosclerosis, hypertension

Secretions :LeptinAdiponectinRBP4

TNF-, IL-6…

Non alcoholic CRPsteatohepatitis PAI1

Visceral adipose tissueSubcutaneous adipose tissue

Obesity complications

Glucose intoleranceInsulin resistance

Pancreas

Fed Fasting

Gut

Triglycerides

Coordination of the regulation of fat deposition and fat

mobilization in white adipose tissue

Triglycerides

LPL

Glut4

Glucose

Glycerol3-phophate

FattyAcids

+Glycerol To liver

To liver,muscle

Insulin

Esterification

Fattyacids

+

+

+

Lipases

- Catecholamines

ANP, BNP

+

Adipocito

ASPAc. Grasos

ApoB VLDL TGApoC II-III- E

Hígado

VLDL

IDL

LDL

CETP

CETP

CE

CE

TG

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 actividadde la lipoproteinlipasa

Obesity complications

Increased synthesis of TG-rich VLDL

Visceral adipose tissue

Glucose intoleranceInsulin resistance

Hyperlipidemia

Liver

Hepatic glucose

production

Glucoseutlization

Skeletalmuscle

Pancreas

FA hepatic flux

Portal and visceral FA

Hyperinsulinemia

VesselsThrombosis

HeartMyocardialperformance

Role of fatty acids in obesity complicationsSubcutaneous adipose tissue

Abdominal FA

Non alcoholic steatohepatitis

Bases moleculares de la resistencia a la insulina en obesidad

Alternate fuel sourcefor brain and other organs Liver

Ketone bodiesand CO2

VLDL Adipose tissue

TG LPL Lipases

Chylomicrons(lymphatic circulation)

Intestinal absorption Muscle,myocardium,kidney cortex,

etc.

LPL

TG

CO2

FA

TG NEFA

NEFA

Overview of fatty acid metabolism

Essays Biochem. 2006;42:89-103.

Hyperinsulinemia

Hypertension

Insulinresistance

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

De Luca & Olefsky, FEBS Lett. 2008,582(1): 97–105

Insulin’s command: “Insulin’s command: “utilize glucose now, build proteins and utilize glucose now, build proteins and store energy for the futurestore energy for the future””

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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.

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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.

Genetics of obesity and its complications

50

Chromosome

GENE

RNA transcript

mRNA in nucleus

mRNA in cytoplasm

Polypeptide

ACTIVE PROTEIN

GENEExon

Intron

TailCap

NUCLEUS

Flowthroughnuclear envelope

CYTOPLASM

Breakdown of mRNA

Translation Broken-down mRNA

Broken-down protein

Cleavage/modification/activation

Breakdownof protein

DNA unpackingOther changes to DNA

TRANSCRIPTION

Addition of cap and tail

Splicing

Niveles de la regulación de la expresión génica

Polygenic obesity

Challenge Discover pertinent genes, gene combinations and interactions

Rare monogenic mutation

LEPR, POMC, PCSK1SIM1, LEP, others

Increase

d energy

INS-VNTR

MC4R

HNF1A

LPLHSL

PPARG

mtDNA

ADRB3

GYS

UCP1

Decre

ased

ener

gy ex

penditu

re

GNB3

APOE

AGT

KCNJ11

MC4R

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

Genetics of human obesityDissection and strategy

EnvironmentGenes

MonogenicHigh penetrance

Monogenic Low penetranceVariable expression

Polygenic

•Rare cases•Syndromes

•Population study•Genetic epidemiology

•Tissue investigation in clinical trials • “omic studies”Example: Adipose tissue analysis

Candidate genes in obese populations

Food intake-centralMonoamines, Peptides&receptors : CART, DRD2, NPY, NPYR, MC3R, POMC, HT2A, AGRP, MC3R, MC4R

Food intake-peripheralPancreatic peptides; Isl1, CCK receptors A&B, GLP1-R

Thermogenesis AR1, 2, 3, AR, CAPN10UCP1, 2, 3

And others ..FAT and glucose metabolism leptin, leptinR,insulin, InsR, SUR, PTP1b, IRS1, Isl1, GCK LPL, HSL, GRL, DGAT, CPT-1apoA4, B, E, CD36, FABP2, LDLR, LIPE, GRL, TNF , TNF-R, adiponectinMaster genes ? PPAR, CDX3, SREBP1

49 Negative associations

30 Positive associations

Morbid obesityLife span Weight gain

Obesity onsetFat mass

Glucid valuesLipid valuesFood intake

Physical activity

Fisiología integral de la obesidad y sus

complicaciones

SNP Databases

•dbSNP http://www.ncbi.nlm.nih.gov/SNP/index.html

•Human Genome Variation Database (HGVbase) http://hgvbase.cgb.ki.se/

TSC: The SNP Consortiumhttp://snp.cshl.org/

Nuevos enfoques

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