Brief review of history
CHILDHOOD OBESITY – EPIDEMIOLOGY, CAUSES,
Historic Museum of Natural Sciences of Vienna
Venus of Willendorf – 25 000 years old
(smbole of fertility?)
CONSEQUENCES
DÉNES MOLNÁR
Statue of pregnant woman (gluteofemoral obesity)
(statue of a godess?)
PTE ÁOK
GYERMEKKLINIKA
Hyppocrit:
Paleolithic Venus Figurines with Prominent Obesity
Name and place
found
Willendorf Austria
Number found
Height
Composition
1
11 cm
Limestone
Many
11,4 cm
Terracotta
Savignano,Italy
1
24 cm
Serpentine
Grimaldi,France
Many
Laussel, France
Many
Lespugue,France
1
Dolni Vestonice
Czechoslovakia
Gagarino,Russia
Many
Kostenki,Russia
Many
Catal Huyak, Turkey
Many
Terracotta
Terracotta
14,7 cm
Ivory
47 cm
Ivory
Ivory
Terracotta
sudden death is more frequent amon
obese, tha in leans.
Obesity leads to infertility.
Brief review of history
Advice of Hypocrite for the obese:
1. Spicy, fatty foods
2.Eat once a day
3.Eat after strenuous physical activity
4. Refrain from drinks except wine
5.Do not have bath, sleep in hard bed
6.Walk much
Advice of Galene:
1.Strong running
2.Strong toweling, massage
3.Bath (no eating during having a bath)
4.Rest then a bath again
5. Eat many times but low energy foods
1
Brief history
Cases of Extraordinary Obesity
Name
19th century: Hotel Dieu – Paris:
Laennec discovers the stethoscope (he
discovered that the auscultation of an obese girl
was easier with a rolled paper)
Gender
Lambert
Bright
Darden
Campbel
Valenzul
Titman
Zadina
Raggio
Maguire
Karns
Nunez
Hall
Pontico
Hughes
Crai
Knorr
King
In 1814: Chapman described pituiter obesity
Prader-Willy sy
Hypoventilation sy (Pickwick sy)
1823 Quatelet index
1950 Chamber: handbook on obesity:
obesity was classified in 3 groups:
1. Infantile
2. Childhood
3. Adult
Age at death
M
M
M
M
M
M
M
F
M
F
F
M
F
M
M
M
F
39
59
22
39
36
29
27
31
28
23
37
35
32
38
46
35
Max. wt(kg)
335
280
462
332
385
318
332
381
385
367
338
343
318
350
485
411
408
381
TRENDS IN OBESITY IN HUNGARY
Overweight among children and
adolescents in the USA
Ages 6-18 (Dóber et al.)
20
18
16
14
12
10
8
6
4
2
0
6 - 11 y
12 - 19 y
Prevalence (%)
16
15
13
10
5
0
19
90
1999
19
80
1963-70 1971-74 1976-80 1988-94
2
Obesity in a developing country - Gambia
35
Prevalence (%)
30
15-24 y
25-34 y
35-44 y
45-54 y
54+ y
25
20
15
10
5
0
Men
Women
Rural
Men
Women
Urban
Etiologic classification of childhood
obesity
• A/ Simple obesity
• Socioeconomic factors
• Lifestyle characteristics (decreased physical
activity, sedentyra lifestyle, dietary factors
[energy dens high fat foods], etc.)
• Genetical factors (susceptibility genes) may
play a role.
van der Sande et al (2001) in press
Aetiological classification of childhood obesity
B/ Secondary obesity
1/ Neuroendocrine:
Hypothalamic lesions, hypothyroidism,
polycystic ovary syndrome,
pseudohypoparathyroidism,
hypogonadism, growth hormone
deficiency, insulinoma, Cushing syndrome
2/ Immobility:
muscular dystrophies, spina bifida, cerebral
paresis, mental retardation, etc.
3/ Psychiatric diseases:
depression, eating disorder, etc.
4/ Iatrogenic:
Steroid treatment, sodium valproate treatment,
anti-thyroid drugs and others
Aetiological classification of childhood obesity
B/ Secondary obesity
5/ Genetic:
Abnormalities of chromosome number:
Down syndrome, Klinefelter syndrome
Rare syndromes associated with obesity:
There are at least 34 rare syndromes.
The most frequent ones:
Prader-Willi, Bardet-Biedl,
Alström and Cohen syndrome
Monogenic obesities:
Protein convertase subtilisin type 1;
Leptin; Leptin receptor; Proopiomelanocortin; Melanocortin 4 receptor
Thyroid hormone receptor beta;
Peroxisome proliferator-activated, gamma
gene mutations
3
Cases of human obesity caused by single-gene mutations
Pérusse L, et al. Obesity Res. 7: 11-29, 1999
Gene
PCSK1
Location
# of
cases
Sex
Age
Obesity
5q15-q21
1
F
3
Severe
LEP
7q31
5
3F, 2M
2-34
Severe
LEPR
1p31
3
F
13-19
Severe
POMC
2p23
2
F&M
3&7
Severe
MC4R
18q21.3
>9
5F, 4M
4-78
Mild to severe
THBR
3p24, 1-p22
1
F
15
Mild
3p25
4
1F, 3M
32-74
Severe
PPARG
THBR=thyroid hormone receptor, beta PCSK1=Protein convertase subtilisin type 1
LEP=leptin, LEPR=leptin receptor; POMC=pro-opiomelanocortin
PPARG=peroxisome proliferator-activated receptor, gamma
MC4R=melanocortin 4 receptor
Leptin receptors
Production sites of Leptin
•
•
•
•
•
•
White adipose tissue
Brown adipose tissue
Placenta
Fetus
Mammary epithelial cells?
Stomach?
•
•
•
•
•
•
•
•
Chorioid plexus
Hypothalamus
Adipose tissue
ß-cells of the pancreas
Lung
Kidney
Skeletal muscle
Small intestine
•
•
•
•
•
•
•
•
Prostate
Testis
Ovaries
Placenta
Fetal tissues
Heart
Adrenal medulla
Liver
4
Leptin in obesity
Energy balance
Pubertal dev.
Haematopoiesis
Immune system
Functions of leptin
Cellular growth
Ð NPY
Ï SNS
ÏLHRH
Leptin receptors in hypothalamus
Reproduction
Ð
Ï
Ð
Ð
Fetal dev.
Food intake
Energy expenditure
Insulin
Cortisol
? Signal suppressing ob gene expression
Leptin
Angiogenesis
{{{{{{{
{{{{{{{{{
{{{{{{{{{{{
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white adipose tissue
Pro-opiomelanocortin gén mutáció
(Krude et al. Nat Gen 19: 155, 1998)
Két páciens került leírásra. Egyik heterozygota volt két
Genetic part of the variance in BMI
(twin studies)
Non-genetic
33%
mutációra: 1. (G7013T, C7133delta) a 3-as exonon, amely
interferál az ACTH és alfa MSH normál szekréciójával, 2.
(C3804A) 2-es exonon amely megszünteti a proopimelanocortin termelődését.
Genetic
67%
Jellemzők: korai, extrém obesitas, mellékvese
elégtelenség, vörös haj
5
Breakdown of the genetic part of the variability in BMI into
metabolic components (Pima studies)
Low MR
12%
Hyperhphagia,
low activity
40%
Low fidgeting
10%
Candidate obesity genes with possible effect on energy
expenditure
Gene
Expressed
Effect
Reference
UCP-1
Brown fat
Thermogenesis ↓
Valve et al.
1998
UCP-2
Ubiquitous
Thermogenesis?
Lipid handling
Thermogenesis?
Lipid handling
Thermogenesis↓
Lipolysis↓
Dulloo 1999
UCP-3
Skeletal
muscle
White and
brown
adipose
tissue
Dopamine
Central
receptor D2
nervous syst
Melanocortin-3- Central
receptor (mouse) nervous syst
ß 3adrenoreceptor
High RQ
5%
Non-genetic
33%
The effect of environment on the
development of obesity
Energy
expenditure↓
Locomotor
activity↓
Dulloo 1999
Strosberg 1997
Tataranni et al.
2001
Butler et al.
2000
Clinical symtoms requiring further
investigations in childhood obesity
Glucosuria
45
Hypertension
Small stature
Cephalalgia, visual disturbances
35
BMI
Arizona
Mexico
Family history for hyperlipidemia, early
cardiovascular event
Dysmorphic features
25
Menstruation disorders
Hirsutism
15
Females
Males
Ravussin et al. Diabetes Care 17: 1067-74,1994
Acanthosis nigricans
Mental retardation
6
Flow chart: Investigation of the obese child
BMI
Overweight
85% < BMI < 97%
At risk
BMI 70-85%
Family history
Blood pressure
Serum cholesterol
Quick change of BMI
Unsuccessful weight
reductions in the
history
Check BMI yearly
Obese
BMI > 97%
·
·
·
·
·
·
·
·
·
·
•
•
•
•
•
Family history
Spec. history a
Body propotions, fat
distribution, striae
distensae b
Height, growth
speed c
Minor anomalies,
polydactylia,
arcdysmorphia,
muscle hypotonia d
Development of
genitalia d
Mental status d
Menstruation
disturbancies,
hirsutism at girls e
Bone age f
Acanthosis
nigricans g
Poz
Neg
.
Neg
.
•
•
Long-term consequences of childhood obesity
•Obesity in adulthood
•Persistence of early co-morbidities
•Tracking of risk factors
•Cardiovascular disease
•Type 2 diabetes mellitus
•Hepatic steatosis and cholelithiasis
•Cancer
•Decreased socio-economic status
Councelling
Followup
.
Primary or „Simple” obesity
Further investigations:
• Blood pressure
• OGTT (blood s glucose + insulin)
• Serum cholesterol, HDL
-, LDL -chol.,
triglyceride
• Hepatic US, hep. func
tion tests
Poz
.
Detailed endocrine
and/or genetic
investigations
a
b
Head injury, headache, visual problams, vertigo ;
Cushing’s sy, Klinefelter sy;
normal stature, endocrine backgroud probably can be excluded (except Klinefelter sy);
;
e
Polycystic ovarian sy;
deficiency);
g
f
Advanced in simple obesity, retarded in endocrine obesities
c
If the child is tall or has
d
Obesity syndromes
t (exception: leptin
Type 2 diabates mellitus/insulin resistance
H E A L T H C O N SE Q U E N C E S O F C H IL D H O O D
O B E SIT Y
Obesity-associated diseases
H igh p rev.
Interm ed. p rev
L ow prev.
Stroke
Hypertension
Heart disease
Hyperlipidemia
Some cancers
Faster grow th
H epatic steatosis
O rthopaedic compl.
Psychosocial
Learning difficulties
Sleep apnoea
Persistence (late on set
Gallbladder dis.
Obesity
Type 2 diabetes
mod erate)
C lustering of risk
factors (M M S)
H igh blood pressure
Osteoarthritis
Gout
Persistence (early onset, Polycystic ovarian sy.
& severe)
D yslipidaemia
Pseudotumor cerebry
C holelithiasis
H yperinsulinaemia
IG T
Skin alterations
Eating disorders
Mood disorders
Sleep disorders
7