obesity as an example of metabolic and endocrine ...vyuka-data.lf3.cuni.cz/cvse1m0001/final english...
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Obesity as an example of metabolic and endocrine
dysfunction of adipose tissue
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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
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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
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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
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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
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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
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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
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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
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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
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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
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E thiopathog enes is of obes ity
Obes ity
E N V IR ON M EN T
G E N OTYPE
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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
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G enotype influenc e on B M I
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Adipose tissue
G enetic backg round for obes ity?
M utation of ob g ene?Leptin
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Neuropeptide Neuropeptide Y Y
Adipose TissueAdipose Tissue
E ffec ts of leptin
LeptinLeptin
HypothalamusHypothalamus
HUNGERHUNGER AACCtivittivityy
Energy expenditureEnergy expenditure
Activity SASActivity SAS
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Arcuate PVN
ReceptorReceptor Melanocortin ReceptorMelanocortin Receptor
FOOD INTAKEFOOD INTAKE
LeptinLeptin
WHITE FATWHITE FAT
ob/ob Mouseob/ob Mouse
α-MSH ?
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• 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
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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
+
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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)
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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 ?
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• In genetically obese db/db mouse plasma leptin levels are normal
• No effect of exogenous leptin
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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
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Treatment w ith leptin
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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
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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
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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
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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
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C ons equenc es of AT dys func tion
Insulin resistance of muscle and liverDiabetes type 2Hypertension
Increased coagulation -trombogenesis
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Abdomina l vers us periphera l obes ity
Small IS adipocytesLarge IR adipocytes
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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
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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)
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Adipose tissue serves as a buffer during p.o. triacylglycerols intakes
Liver, muscle
Adiposetissue TAG,
NEMK
Fat intake
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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)
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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
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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
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Analysis of 44 000 transcripts- time course of dietary intervention
Capel, Klimcakova et al, Diabetes 2009
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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
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The best prevention of cardiovascular disease and diabetes is the appropriate quantity of adipose tissue together with healthy lifestyle and diet.