PATHOFYSIOLOGIE VAN OBESITAS: OORZAAK EN GEVOLG - kids 0

PATHOFYSIOLOGIE VAN OBESITAS:
OORZAAK EN GEVOLG
Lisbeth Mathus-Vliegen
Maag-Darm-Leverarts
Academisch Medisch Centrum
Universiteit van Amsterdam
e.mathus-vliegen@amc.uva.nl

PATHOFYSIOLOGIE VAN
OBESITAS:
OORZAAK

PATHOGENESIS OF OBESITY
ENERGY INTAKE = ENERGY EXPENDITURE + ∆ ENERGY STORES
Energy lost in faeces
Energy lost in urine
Food
Energy intake
Energy in circulation
Energy metabolised
Basal metabolic rate Physical activity Thermogenesis
60-75% 10-30%
7-13%
diet-induced (5-22%)
cold-induced
drug-induced
Energy expenditure (heat production)
Body energy stores
fat (77%), protein
(22%), glycogen (1%)

SECULAR INCREASE IN OBESITY
putative contributors
The Big Two reduced physical activity
food manufacturing and
marketing
Physical education classes at school
TV viewing
Vending machines in schools
Fast-food availability
High-fructose corn sugar
Portion size Keith et al., Int J Obes 2006;30:1585-1594

PERCENTAGE OF ALL TRIPS BY CYCLING
AND WALKING
%
30
25
20
15
10
5
0
Cycling
Walking
Netherlands UK & Wales USA

CHANGE IN
SERVING SIZE
OF SODA
Calories per serving
without ice (Colas
12.5 kcal per 180 ml)
CHANGES IN
SERVING
SIZE OF FRIES
*Between 1990 and 2000
large became medium

SECULAR INCREASE IN OBESITY
putative contributors
Causal influences Increased frequency
sleep debt
endocrine disruptors
reduction in variability of ambient temperature
decreased smoking
pharmaceutical iatrogenesis
changes in distribution of ethnicity and age
increased gravida age
intrauterine and intergenerational effects
greater reproductive fitness yielding selection
associative mating and floor effects
Keith et al., Int J Obes 2006;30:1585-1594

SECULAR INCREASE IN OBESITY
putative contributors
Adenovirus-36
Increased childhood depression
Insufficient calcium (dairy) consumption
Hormones in agricultural species
Shift work
Not breast feeding
Keith et al., Int J Obes 2006;30:1585-1594

PUTATIVE CONTRIBUTORS TO THE SECULAR INCREASE IN
OBESITY
PBDE polybrominated diphenyl ethers in breast milk, AC = air conditioning
Keith et al., Int J Obes 2006;30:1585-1594

EPIDEMIOLOGIC MODEL OF OBESITY:
in a susceptible host, the effects of different agents
produce the disease of obesity
Agent:
Ease of inactivity
Agent:
Drugs
Agent:
Viruses
Agent:
Food
Host
genetic factors, intrauterine
imprinting, physiologic control
Agent:
Toxins
Obesity
gene-environment synergism
Bray & Champagne JADA 2005;105:S17-S23

PATHOGENESIS OF OBESITY
Obesogenic environment promoting energy dysbalance
*abundance of highly processed food
increasing portion size
instant gratification
“more for less” mindset
*discouragement of physical activity
Genetics 50% of the contribution of fatness and fat
distribution is genetic
Brain-periphery-gut axis
Adipose tissue as endocrine organ

AETIOLOGY OF OBESITY
Energy dysbalance
Genetics
Brain-periphery-gut axis
Adipose tissue as endocrine organ

BEWIJS VOOR GENETISCHE BASIS
Familie studies (pets; echtgenotes)
Tweeling studies (eeneiïg en twee-eiïg; apart
opgevoed; overvoeding)
Adoptie studies
Geïdentificeerde genen

GENETICS VERSUS ENVIRONMENT
Adoption and family studies 0.25-0.50
Twin studies 0.70
Discrepancy upwardly biased estimates in twins
non-additive genetic effects (dominance,
age-gene, gene-environment and genegene
interactions)
Twins reared apart
93 Swedish pairs 0.68
34 English pairs 0.61
17 Finnish pairs 0.65
10 Japanese pairs 0.73
20 US and Danish pairs 0.85
30-70% of the variation in BMI is genetic

Author
Jackson
Montague
Strobel
Clement
Krude
Ristow
Yeo
Vaisse
HUMAN OBESITY WITH EVIDENCE FOR
OBESITY-PROMOTING GENES
Gene
Prohormone
convertase 1
OB (Lep)
OB (Lep)
OB-R (Lep-R)
POMC (pre-proopiomelanocortin)
PPAR-γ-2
MC4R
MC4R
N
families
1
1
1
1
2
4
1
1
N
cases
1
2
3
3
2
4
2
6
Remarks
Same as deficient
carboxypeptidase E
Massive obese child
No puberty
No puberty
Red hair, age

PLEIOTROPIC OBESITY SYNDROMES
• Obesity in families
• 30 Mendelian disorders
– Obesity
– Mental retardation
– Dysmorphic features
– Organ-specific developmental abnormalities
• Very rare: 1:25.000 - < 1:100.000; 0.5:1000 males
• Autosomal dominant: Prader-Willi, Albright
• Ausosomal recessive: Alstom, Cohen, Bardet-Biedl
• X-linked: fragile X, Wilson-Turner

AETIOLOGY OF OBESITY
Energy dysbalance
Genetics
Brain-periphery-gut axis
Adipose tissue as endocrine organ

Korner & Leibel NEJM 2003;39:926-7
stimulating
inhibiting

HYPOTHALAMIC PEPTIDES AND
ENERGY HOMEOSTASIS
orexigenic anorectic
Body weight
Fat mass
Feeding
Thyrotropic axis
Metabolic rate
Physical activity
Insulin output
Adrenal axis
NPY
↑
↑
↑
↓
↓
↓
↑
↑
AgRP
↑
↑
↑
↓
↓
↓
↔
↔
αMSH
↓
↓
↓
↑
↑
-
↔
-
CART
↓
↓
↓
↓ ?
?
↑
↓
↑
CRH
Sainsbury et al., Best Pract Res 2002,16:623-637 ↔ no effect, ↓decrease, ↑increase
↓
↓
↓
-
↑
-
↓
↑

AETIOLOGY OF OBESITY
Energy dysbalance
Genetics
Brain-periphery-gut axis
Adipose tissue as endocrine organ

FAT CELL DEVELOPMENT
15 wk gestation development of adipocyte
Third trimester rapid increase in fat cell number and size
increase in % body fat from 5 to 15%
Term birth fat one-six of infant’s weight
5 billion adipocytes, 16% of adult
Infancy fat cell increase in size
Age 2-14 lean fat cell size unchanged, small increase in
number in age 2-10
obese fat cell increase in size, triggering an
increase in number when lipid content
> 1µg lipid/cell
weight loss rate of new fat cell formation slows down
but still at a greater rate than in lean

ADIPOSE TISSUE
Energy storage
Insulation from temperature and trauma
Endocrine organ influenced by total fat mass and fat distribution
* immune hormones: TNF-α, IL-6
* cardiovascular hormones: PAI-1, RAS
* metabolic hormones: resistin, adiponectin,
FFA
* endocrine hormones: leptin, cortisol,
androgens, oestrogens

ADIPOSE TISSUE
Energy storage
Insulation from temperature and trauma
Endocrine organ influenced by total fat mass and fat distribution
* immune hormones: TNF-α, IL-6
* cardiovascular hormones: PAI-1, RAS
* metabolic hormones: resistin, adiponectin,
FFA
* endocrine hormones: leptin, cortisol,
androgens, oestrogens
Chronic low grade of inflammation, insulin resistance,
hyperinsulinaemia, altered innate immunity

PATHOFYSIOLOGIE VAN
OBESITAS:
GEVOLG

PATHOPHYSIOLOGY OF DIABESITY
Coexistence of type 2 diabetes and obesity
Worldwide 285 million subjects with diabetes, projected to be 438 million in 2030
> 90% type 2 diabetes and of these > 90% overweight, obese or a history of being so
< 50% HbA1c < 7% Bailey BMJ 2011, 342: d1996

RELATIVE RISK (RR) OF HEALTH PROBLEMS
ASSOCIATED WITH OBESITY
Greatly Moderately Slightly
increased (RR > 3) increased (RR > 2-3) increased (RR 1-2)
Diabetes Coronary heart disease Certain cancers
Gallbladder disease Hypertension Reproductive
Dyslipidaemia Osteoarthritis (knee) hormone (PCOS)
disturbances
Insulin resistance Hyperuricaemia Impaired fertility
Breathlessness Gout Low back pain
Sleep apnoea Increased
anaesthetic risks
Waist Fetal defects
WHO/IOTF 1998
METABOLIC SYNDROME

RELATIVE RISK (RR) OF HEALTH PROBLEMS
ASSOCIATED WITH OBESITY
Greatly Moderately Slightly
increased (RR > 3) increased (RR > 2-3) increased (RR 1-2)
Diabetes Coronary heart disease Certain cancers
Gallbladder disease Hypertension Reproductive
Dyslipidaemia Osteoarthritis (knee) hormone (PCOS)
disturbances
Insulin resistance Hyperuricaemia Impaired fertility
Breathlessness Gout Low back pain
Sleep apnoea Increased
Gastro-oesophageal reflux disease anaesthetic risks
Gallbladder and bile duct stones
Fetal defects
Acute pancreatitis;pancreas cancer
NAFLD; NASH; liver cancer
Colonic polyps; colonic cancer

RELATIVE RISK (RR) OF HEALTH PROBLEMS
ASSOCIATED WITH OBESITY
Greatly Moderately Slightly
increased (RR > 3) increased (RR > 2-3) increased (RR 1-2)
Diabetes Coronary heart disease Certain cancers
Gallbladder disease Hypertension Reproductive
Dyslipidaemia Osteoarthritis (knee) hormone (PCOS)
disturbances
Insulin resistance Hyperuricaemia Impaired fertility
Breathlessness Gout Low back pain
Sleep apnoea Increased
Gastro-oesophageal reflux disease anaesthetic risks
Gallbladder and bile duct stones
Fetal defects
Acute pancreatitis;pancreas cancer
NAFLD; NASH; liver cancer
Colonic polyps; colonic cancer

Increased prevalence
(8-18%) in insulinresistant
diabetes
Confounders as
independent risk factors
for cancer:
Physical inactivity
Obesity
Diabetes treatment types
High saturated-fat diet
CANCER AND INSULIN
↔ Cancer of ↔
Increased prevalence
• Breast
in obesity and
• Colorectum
metabolic syndrome
• Pancreas
• Liver
• Genitourinary tract
Non-Hodgkin lymphomas
Worst outcome vs non-diabetics:
increased cancer-site specific mortality (breast, endometrium, colorectum)
reduced sensitivity to anticancer therapy
Landriscina & Esposito J Gastrointest Oncol 2011; 2: 11-12

Increased prevalence
(8-18%) in insulinresistant
diabetes
Confounders as
independent risk factors
for cancer:
Physical inactivity
Obesity
Diabetes treatment types
High saturated-fat diet
CANCER AND INSULIN
↔ Cancer of ↔
Increased prevalence
• Breast
in obesity and
• Colorectum
metabolic syndrome
• Pancreas
• Liver
• Genitourinary tract
Non-Hodgkin lymphomas
INSULIN RESISTANCE
HYPERINSULINEMIA
Worst outcome vs non-diabetics:
increased cancer-site specific mortality (breast, endometrium, colorectum)
reduced sensitivity to anticancer therapy
Landriscina & Esposito J Gastrointest Oncol 2011; 2: 11-12

CHRONIC HYPERINSULINEMIA
• Cancer initiation and progression due to direct mitogenic
activity of insulin
• Indirect stimulation of cancer cells by increasing other
modulators of proliferation (insulin-like growth factor-1
(IGF-1) and sex hormones)
Cancer cells increased expression
of insulin and IGF-1 receptors
Inability to down-regulate receptors
in the presence of hyperinsulinemia
Insulin and IGF-1 strong activators
of P13K/AKT and MAPK pathways
Proliferation and anti-apoptosis
Tumor progression, drug resistance,
poor outcome
Landriscina & Esposito J Gastrointest Oncol 2011; 2: 11-12

GROWTH PROMOTING EFFECT OF INSULIN-
RECEPTOR SIGNALING
PTEN

• AMPK activation
METFORMIN
– Reversal hyperglycemia, insulin resistance and hyperinsulinemia
– Reversal mitogenic effects of hyperinsulinemia
• Modulation of insulin and IGF-1 signaling
• Inhibition of mTOR kinase pathway
• Interference with tumor angiogenesis
• Induction of cell cycle arrest and apoptosis
• Antiproliferative effect
• Enhancement of chemotherapeutic cytotoxicity
Landriscina & Esposito J Gastrointest Oncol 2011; 2: 11-12

PATHOFYSIOLOGIE VAN OBESITAS:
conclusies
ONTSTAANSWIJZE
Bij het ontstaan van obesitas speelt de energiedysbalans
met teveel energie inname ten opzichte van de energie
behoefte een primaire rol
Genetische invloeden bepalen de gevoeligheid van het
individue
Talrijke andere factoren uit de veranderde obesogene omgeving
dragen bij zoals een constante omgevingstemperatuur,
toegenomen portiegrootte, antidepressiva, stoppen met roken,
geen borstvoeding etc.

PATHOFYSIOLOGIE VAN OBESITAS:
conclusies
GEVOLGEN
De met obesitas geassocieerde ziekten zijn te verklaren
door de rol van het vetweefsel als endocrien orgaan
Insuline resistentie staat niet alleen centraal bij het
ontstaan van diabetes type 2 maar ook bij de genese van
de aan obesitas geassocieerde verhoogde kans op
carcinomen