Obesity as an example of metabolic and endocrine

dysfunction of adipose tissue

Outline

1. Obesity-definition, relationship to health

2. E thiopathogenesis of obesity

3. Communication between adipose tissue and the rest of the body– Cytokines– Free fatty acids

4. The significance of weight loss

What is obes ity?

excessive accumulation of fat, i.e. expansion of adipose tissue

Body Mass Index

B M I = w eig ht (kg ) /heig ht2 (m)

Example: BMI = 75 / 1.82 = 23.1 kg/m2

C las s ific a tion of obes ity- WHO

Classification

Normal weight

Overweight:

Obesity:Degree IDegree IIDegree III

BMI(kg/m2)

18.5 - 24.9

25.0 - 29.9

30.0 - 34.935.0 - 39.9

≥ 40

Risk of associated disorders

Average

Elevated

MiddleHigh

Very high

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4

<18.5

18.5-

20.4

20.5-

21.9

22.0-

23.4

23.5-

24.9

25.0-

26.4

26.5-

27.9

28.0-

29.9

30.0-

31.9

32.0-

34.9

35.0-

39.9

Kardiovaskulární onemocnění

Rakovina

Všechny ostatní příčiny

Relative risk of death

≥40.0

Mortality increases with body mass index

BMI Calle EE et al. N Engl J Med 1999; 341: 1097-195

0055

10101515202025253030353540404545

<22.9<22.9 22.9-22.9-24.624.6

24.6-24.6-25.925.9

25.9-25.9-27.927.9

27.9-3227.9-32 32-4032-40 >40>40

Obesity is a risk factor of diabetes 2nd typere

lat iv

e r is

kre

lat iv

e r is

k

BMI (kg/mBMI (kg/m22))Chan et al, Diabetes Care, 1994Chan et al, Diabetes Care, 1994

Obesity is associated with increasingprevalence of hypertension

National Institutes of HealthNHLBI Clinical Guidelines.1998

*STK´ ≥ 140 mmHg, DTK ≥ 90 mmHgnebo užívání antihypertenziv

0

5

1015

20

25

3035

40

45 Muži Ženy

Prevalence hypertenzekorigovaná vzhledem k věku*

< 25 25-26 27-29 ≥ 30 < 25 25-26 27-29 ≥ 30BMI

18.222.5

25.2

38.4

16.5

21.9 24.0

32.2

22,648,8

28,6

25,6

30,9

43,5

men women

Preva lenc e of obes ity and overw eig ht in Č R

Norma BW(BMI 18,5-25)

overweight (BMI 25-30)

obesity(BMI >30)

n = 1174 n = 1275

Hainer V. et al., Progress in obesity research, 1999 podle Czech Monica 1997

Secular trends in obesity in the UK

0

5

10

15

20

25

1980 1986 1991 1998

Year of Survey

Prev

alen

ce o

f obe

sity

MenWomen

Health Survey for England, 1998

OBESITY RATES COULD DOUBLE IN30 YEARS

n n n

nn

n

l

llll

l

t

oo

u

u

u u

n

l

o

50

40

30

20

10

0

% o

f pop

ulat

ion

BM

I >3

0

1960 1970 1980 1990 2000 2010 2020 2030Year

USA

England

Australia

Mauritius

Brazil

l

u

E thiopathog enes is of obes ity

Obes ity

E N V IR ON M EN T

G E N OTYPE

E volution of energ y bilanc e

L. Cordain, et al: Int. J. S ports Med. (1998)

averag e/day pa leolithe 21.c entury

Physical activity 1240 kcal 555 kcal

Energy intake 2900 kcal 2030 kcal

Energy intake Energy expenditure

Astrup et al. Int J Obes 1998; 22(1): S 30-S 35

G enotype influenc e on B M I

Adipose tissue

G enetic backg round for obes ity?

M utation of ob g ene?Leptin

Neuropeptide Neuropeptide Y Y

Adipose TissueAdipose Tissue

E ffec ts of leptin

LeptinLeptin

HypothalamusHypothalamus

HUNGERHUNGER AACCtivittivityy

Energy expenditureEnergy expenditure

Activity SASActivity SAS

Arcuate PVN

ReceptorReceptor Melanocortin ReceptorMelanocortin Receptor

FOOD INTAKEFOOD INTAKE

LeptinLeptin

WHITE FATWHITE FAT

ob/ob Mouseob/ob Mouse

α-MSH ?

• Genetically obese mouse (ob/ob) express mutation of ob genu and no leptin secretion is present

• Administratio of leptin induces a decrase in food intake and redction of body weight

Neuropeptide Neuropeptide Y Y

Adipose TissueAdipose Tissue

Phys iolog ic a l reg ula tion of leptin produc tion

LeptinLeptin

HypothalamusHypothalamus

HHladlad AAkktivittivitaa

Energetický výdejEnergetický výdej Aktivita SASAktivita SAS

+

Log

Seru

m L

epti

nLo

g Se

rum

Lep

tin

Body Fat (%)Body Fat (%) 2020 4040 6060

100.0100.0

10.010.0

1.01.0

Plasma leptin levels are increased in obese subjects

Considine RV, N Engl J Med 1996;334:292-5Considine RV, N Engl J Med 1996;334:292-5

1010 2020 3030 4040 5050 6060 7070

100100

8080

6060

4040

2020

00

Body Fat (%)Body Fat (%)

Seru

m L

eptin

(ng

/mL)

Seru

m L

eptin

(ng

/mL)

Arcuate PVN

ReceptorReceptor Melanocortin ReceptorMelanocortin Receptor

FOOD INTAKEFOOD INTAKE

LeptinLeptin

WHITE FATWHITE FAT

db/db Mouse,db/db Mouse,““Fatty” Zucker RatFatty” Zucker Rat

α-MSH ?

• In genetically obese db/db mouse plasma leptin levels are normal

• No effect of exogenous leptin

Obes ity c aus ed by mutation of ob g ene and abs enc e of leptin in pla s ma w as found in humans

3535

3030

2525

2020

1515

1010

55

PatientPatient

00

33 66 99 1212 1818 2121 3636 484842423030

Age (months)Age (months)

KgKg

Treatment w ith leptin

Other roles of leptin

• S exual development– Regulation of fertility– Amenorhea upon extreme reduction of

adipose tissue (mental anorexia, professional level of sport activities)

• S upport of pregnancy

• Regulation of imunity

Imunoregulation IL-1 IL-1b IL-8 IL-10 Macrophage chemoatractant protein-1 Nerve growth factor

Growth factorsTransforming growth factor β Vascular endothelium growth factorHepatocyte growth factorAngiotensinogen

Proteiny akutní fáze Haptoglobin Serum amyloid A C-reactive protein

Hemocoagulation Plasminogen activator inhibitor-1

Adipose tissue

Insulin signaling Adiponectin Leptin Visfatin IL-6 TNF-α Resistin Adipsin Retinol binding protein 4

How does AT c ommunic ate w ith the

res t of the body?

Free fatty acids

Lean ATadipocytes preadipocyte

s

Endothelial cells

macrophagesmonocytes

lymphocytes

S tem cells

Weig ht g a in

Obes e AT

Pro-inflammatory

cytokines

Anti-inflammatory cytokines

Anti-inflammatory cytokines

Pro-inflammatory cytokines

Weig ht g a in

C ellula r c ompos ition of AT

M olec ular c aus es of AT endoc rine dys func tion ?

Hypertrophic adipocytesHypoxia

Increased energy substrate flow and stress of endoplasmic reticulum

N ot know n

C ons equenc es of AT dys func tion

Insulin resistance of muscle and liverDiabetes type 2Hypertension

Increased coagulation -trombogenesis

Abdomina l vers us periphera l obes ity

Small IS adipocytesLarge IR adipocytes

Lipoatrophic mouse model (A-ZIP/F-1 mouse)

Mice lacking adipose tissue are•diabetic•severely insulin resistant•heavy (large muscle and organ

mass)•have elevated TG in muscle and liver

Kim J et al. (2000) J Biol Chem 275:8456-60

PARADOX

Lipoatrophic mouse model (A-ZIP/F-1 mouse)

Kim J et al. (2000) J Biol Chem 275:8456-60

Transplantation of adipose tissue:

•reverses diabetes•reverses insulin resistance•reduces TG in muscle and

liver(in a dose-dependent manner)

Adipose tissue serves as a buffer during p.o. triacylglycerols intakes

Liver, muscle

Adiposetissue TAG,

NEMK

Fat intake

The meaning of w eig ht los s

5-10%

Blood pressure

worseningworsening Lipid profile

worseningworsening IS, glycemia, diabetes

Risk of thrombogenesis

Inflammatory markers

ObesityObesity

Després JP, BMJ 2001;322:716-20Després JP, BMJ 2001;322:716-20

Risk of cardiovacular diseases

improvementimprovement

improvementimprovement

w eig ht reduc tion(diet, exerc is e,

pharmac otheraphy)

M ild w eig ht los s reduc es a ris k of DM I

development about 30%

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

1.01.0RR

elat

ive

risk

elat

ive

risk

controlcontrol(no weight loss)(no weight loss)

ddietiet exerciseexercise ddietiet ++exerciseexercise

Weight loss 4.5 kg

Wing RR et al, Diabetes Care 1998Wing RR et al, Diabetes Care 1998

Weig ht los s extends life of diabetic s

• 20% reduction of mortality• 30% reduction of mortality associated with

DMII

Weight loss (kg) in first 12 months

Lean et al. Diabet Med, 1990; 7: 228-33

Exp

ecte

d lif

espa

n (y

ears

)18

16

14

12

10

8

00 2 4 6 8 10 12 14 16

95% confidence interval

Analysis of 44 000 transcripts- time course of dietary intervention

Capel, Klimcakova et al, Diabetes 2009

S ummary

• Obesity is associated with worsening of metabolic and endo/paracrine functions of AT– Reduced ability to accumulate lipids– Enhanced secretion of proinflammatory

cytokines

• Already mild 5-10% weight loss has substantial positive effects on health

The best prevention of cardiovascular disease and diabetes is the appropriate quantity of adipose tissue together with healthy lifestyle and diet.