EATING DISORDERS
ZLA 5. 4. 2018
HISTORY
 Lipostatic hypothesis (Kennedy 1953) –
adipose tissue products specific „lipostatic“
factor
 Glukostatic hypothesis (Mayer and Thomas
1967) – changes in glycemia lead to
stimulation /inhibition of food intake (brain
and liver)
 Combination of both hypotheses???
IT IS NECESSARY TO DISTINGUISH COMMON
HOMEOSTATIC REGULATIONS OF FOOD INTAKE AND
HEDONIC REGULATIONS
SIMPLIFIED
SCHEME OF
HOMEOSTATIC
REGULATIONS OF
FOOD INTAKE.
SUBSTANTIAL SIGNALS
ORIGINATE FROM GIT
(GHRELIN, CCK, PYY),
ADIPOSE TISSUE (LEPTIN,
OTHER ADIPOKINES) AND
PANKREAS (INSULIN,
GLUKAGON)
Gut hormones and the regulation of energy homeostasis
Kevin G. Murphy and Stephen R. Bloom
Nature 444, 854-859(14 December 2006)
CENTRAL AND PERIPHERAL CIRCUITS IN REGULATION OF
FOOD INTAKE
PYY
 Peptide YY is related to the pancreatic peptide family by having 18 of its 36 amino
acids located in the same positions as pancreatic peptide. The two major forms of
peptide YY are PYY1-36 and PYY3-36, which have PP fold structural motifs. However,
the most common form of circulating PYY immunoreactivity is PYY3-36, which binds
to the Y2 receptor (Y2R) of the Y family of receptors. Peptide YY3-36 (PYY) is a linear
polypeptide consisting of 36 amino acids with structural homology to NPY and
pancreatic polypeptide.
 PYY is found in L cells in the mucosa of gastrointestinal tract, especially in ileum and
colon. Also, a small amount of PYY, about 1-10%, is found in the esophagus,
stomach, duodenum and jejunum. PYY concentration in the circulation increases
postprandially (after food ingestion) and decreases by fasting. In addition, PYY is
produced by a discrete population of neurons in the brainstem, specifically
localized to the gigantocellular reticular nucleus of the medulla oblongata.
 PYY exerts its action through NPY receptors; it inhibits gastric motility and increases
water and electrolyte absorption in the colon. PYY may also suppress pancreatic
secretion. It is secreted by the neuroendocrine cells in the ileum and colon in
response to a meal, and has been shown to reduce appetite. PYY works by
slowing the gastric emptying; hence, it increases efficiency of digestion and
nutrient absorption after a meal.
Drug Insight: the functions of ghrelin and its potential as a multitherapeutic hormone
Masayasu Kojima and Kenji Kangawa
Nature Clinical Practice Endocrinology & Metabolism (2006) 2, 80-88
REGULATION OF FOOD INTAKE
1994 – ADIPOSE TISSUE IS ABLE TO PRODUCE
HORMONS ITSELF – LEPTIN DISCOVERY
Mutation of ob gene coding for
leptin is leading to significant
obesity in mouse
Zhang et al, Nature, 1994.
Leptin therapy led
to normalized body
weight and/or
fertility of these
mutated mice
These factors are produced by adipocytes, but
also by macrophages, fibroblasts, endothelial
cells and other cells in adipose tissue
They are usually:
1. Proinflammatory (TNF-, IL-6,
resistin)
2. Anti-inflammatory (adiponektin)
They are very important in
metabolic regulations
WAT produces adipokines
To date, a lot of adipose tissue-derived factors has been described. These factors with pleiotropic functions in many processes including
regulation of energy metabolism, inflammation, food intake, insulin sensitivity etc. Markedly contribute to metabolic regulations and its
pathologies.
In food intake and
especially in
postprandial
supression of
appetite, many
substances
produced in GIT
play substantial
roles.
Holst B, Schwartz TW. 2004
Food Intake and GIT…
OBESITY IS ASSOCIATED WITH LOCAL
INFLAMMATORY RESPONSE IN FAT
mRNAexpression
0,0
0,2
0,4
0,6
0,8
Control
Obese
Subcutaneous fat Visceral fat
*
* °
ADIPONECTIN
Copyright ©2006 American Society for Clinical Investigation
Holick, M. F. J. Clin. Invest. 2006;116:2062-2072
Regulation of gene expresssion by VDR
o Vitamin K2 is sunstantial cofactor for γ-carboxylase, enzyme which
catalyses conversion of specific residuals of glutamic acid to Gla
residuals
o Vitamin K2 is necessary for γ-carboxylation of proteins of bone matrix
which contain Gla as MGP (= matrix Gla protein) a osteokalcin.
o Uncompleted γ-carboxylation of osteocalcin and MGP during
vitamin K decrease lead to osteoporosis and high risk of fractures.
Vitamin K2 stimulates synthesis of osteoblastic markers and bone
deposition.
o Vitamin K2 decreases bone reabsorbtion by inhibition of osteclasts
formation and by decrease of their resorbtion activity.
o Vitamin K2 treatment induces osteoclast apoptosis, but inhibits
osteoblasts apoptosis which is leading to increased bone formation.
o Vitamin K2 supports osteocalcin expression ( increases its mRNA)
which can be further modulated by 1, 25-(OH)2 vitamin D3.
Vitamin K and bones
Vitamin K2 is transcription
regulator od specific bone
genes, functioning using SXR
which will lead to increase of
osteoblastic markers
expression.
SXR originally identifies as
xenobiotic sensor…
OSTEOPOROSIS
 is a skeletal disease characterised by low bone mass
and microarchitectural deterioration with a resulting
increase in bone fragility and hence susceptibility to
fracture.
 It is an important public health issue because of the
potentially devastating results and high cumulative
rate of fractures; in white populations, about 50% of
women and 20% of men older than 50 years will
have a fragility fracture in their remaining lifetime.
Osteoporosis
OSTEOPOROSIS
 Oestrogen has a central role in normal physiological remodelling, and
oestrogen deficiency after the menopause results in a remodelling
imbalance with a substantial increase in bone turnover.
 This imbalance leads to a progressive loss of trabecular bone, partly
because of increased osteoclastogenesis.
 Enhanced formation of functional osteoclasts seems to be the result
of increased elaboration of osteoclastogenic proinflammatory
cytokines such as interleukin-1 and tumour necrosis factor, which are
negatively regulated by oestrogen.
 A direct effect of oestrogen in accelerating osteoclast apoptosis has
also been attributed to increased production of transforming growth
factor β.
OSTEOPOROSIS - CAUSES
 Glucocorticoids excess
 Estrogene deficiency
 Vitamin K2 deficiency?
Cortisol
generally
antagonizes
insulin …
a) Several endogenic factors support
osteoblastogenesis against adipogenesis.
b) High levels of cortisol prefer adipogenesis
to osteoblastogenesis
Low [GC] low (physiological) concentrations of
glucocorticoids, GH- growth hormone, IGF-1
insulin-like
growth factor-1, FGF-2 fibroblast growth
factor-2, IL-11 interleukin-
11, CT-1 cardiotrophin-1, OSM oncostatin M,
OB osteoblast, AD-adipocyte
Equilibrium between osteoblastogenesis (OB) and adipogenesis
(AD)
COMMON ADVERSE EFFECTS OF GLUCOCORTICOID THERAPY
 There is substantial and accelerated decreases in bone mineral density (BMD)
with oral glucocorticoid therapy, most pronounced in the first year, with
trabecular bone more quickly affected than cortical bone.
 Even after only 2 months of high-dose glucocorticoids, studies show markedly
decreased BMD at the lumbar spine, femoral neck and whole body, with the
greatest loss in the trabecular lumbar vertebrae.
 In light of the high incidence of glucocorticoid-induced osteoporosis and
associated fractures, screening and treatment rates for glucocorticoidinduced
osteoporosis has come under substantial scrutiny.
 Less than 50% of patients receiving long-term glucocorticoids have been
evaluated for osteoporosis, and less than 25% have been treated. There is
great variability among clinicians in both the awareness of glucocorticoidinduced
osteoporosis and the importance of prevention and treatment as the
standard of care.
 The use of antiosteoporotic medication was observed to be most common
among postmenopausal women, where it approached 50%.
COMMON ADVERSE EFFECTS OF GLUCOCORTICOID THERAPYGLUCOCORTICOID-INDUCED
OSTEOPOROSIS
 Glucocorticoid-induced osteoporosis is the most common type
of iatrogenic osteoporosis and a frequent cause of secondary
osteoporosis.
 An estimated 50% of patients taking glucocorticoids for longer
than 6 months will develop secondary osteoporosis .
 The absolute risk for glucocorticoid-induced osteoporosis is
higher in patients aged 65 years or older given their baseline
age-related fracture risk, although the relative risk of fracture
related to glucocorticoid use may be even higher in patients
under 65 .
PATHWAYS OF TRANSCRIPTION FACTORS PARTICIPATING
IN NUTRITION BASED INTERACTIONS
SIZE AND ENDOCRINE PROFIL OF ADIPOCYTES IS
CORRELATED WITH THE WHOLE ADIPOSITY
Malnutrition
(Anorexia nervosa)
Normal state (slight overweight)) Obesity
DIAGNOSTIC CRITERIA OF OBESITY (BMI)
Weight (kg)
Height (m2)
WHO, 1998
Classification BMI (kg/m2) metabolic rate
Normal body weight 18.524.9 average
Overweight 2529.9 increased
Obesity I 30.034.9 middle
Obesity II 35.039.9 high
Obesity III 40.0  very high
BMI =
WAIST SIZE SEEMS TO BE THE BEST INDICATOR OF
VISCERAL OBESITY
Women
>88 cm = highly increase risk1
>80 cm = higher risk1
Men
>102 cm = highly increased risk1
>94 cm = higher risk1
1Lean MEJ, et al. Lancet;1998:351:853–6
cm
STANDARDISED PREVALENCE OF OBESITY 2008
Has obesity genetic background?
OBESITY
 Argumenst why yes:
 Family aggregation
 Twin studies (higher concordance
of obesity incidence in MZ
compared to DZ twins)
 Large family studies
HERITABILITy of OBEsITY
Family studies 30-50%
Adoption studies 10-30%
Twin studies 50-90%
GENETICS OF OBESITY
IS OBESITY DONE BY
CULTURAL EATING HABITS?
GENETICS OF OBESITY – ARGUMENTS WHY NOT
pleiotropic syndromes with obesity
„monogenic“ syndromes with obesity
polygenic (complex) syndromes
CLASSIFICATION OF OBESITY SYNDROMES
 About 30 syndromes, in which
obesity represents constant
component
PLEIOTROPIC SYNDROMES WITH OBESITY
MONOGENIC SYNDROMES WITH OBESITY
N C Med J. 2013; 74(6):530-533
Prof.Stephen O'Rahilly, MD and I. Sadaf Farooqi, MD
Heiko Krude, Heike Biebermann, Werner Luck,
Rüdiger Horn, Georg Brabant & Annette Grüters
Congenital leptin defficiency
before and
after treatment
POMC mutation
(cave hair)
MONOGENIC OBESITY SYNDROMES
SY PRADER- WILLI AS A CLINICAL EXAMPLE
 Hypotonic children, mental
retardation, small figure,
behavioral complacations
(hyperphagy as a result of
incontrolled appetite – one
of the most common
causes of children obesity)
 Loss of expression of
paternally imprinted genes
at15q11.2-q13 chromosome
as a result of microdeletion
in the region.
 Susceptibility genes
Genome wide scans
Association studies focused on
susceptibility (candidates)
genes for obesity
Metaanalysis of candidate
genes identified by
different methods
QTL
(quantitative trait locus)
OBESITY AS A COMMON (COMPLEX) DISEASE
FUTURE
 BMC Med. 2017; 15: 50.
 Published online 2017 Mar 7. doi: 10.1186/s12916-017-0800-1
 PMCID: PMC5340003
 Developmental pathways to adiposity begin before birth and are
influenced by genotype, prenatal environment and epigenome
 Xinyi Lin,#1 Ives Yubin Lim,#1,2 Yonghui Wu,1 Ai Ling Teh,1 Li Chen,1 Izzuddin
M. Aris,1 Shu E. Soh,1,3 Mya Thway Tint,2,3 Julia L. MacIsaac,4 Alexander M.
Morin,4 Fabian Yap,5 Kok Hian Tan,5 Seang Mei Saw,6,7,8 Michael S. Kobor,4
Michael J. Meaney,1,9 Keith M. Godfrey,10 Yap Seng Chong,1,2 Joanna D.
Holbrook,1 Yung Seng Lee,1,3,11 Peter D. Gluckman,1,12 Neerja Karnani,1,13
and on behalf of the GUSTO study group
OBESITY AS A COMPLEX DISEASE
 Genetic, epigenetic and prenatal
environmental factors are linked to offspring
size and adiposity at birth and in early
childhood.
 Individual prenatal environmental influences
on birth weight was identified; some of these
prenatal environment variables maternal
ppBMI, GWG („Gestational Weight Gain“) and
glucose levels continued to associate with
offspring size and adiposity in early childhood.
OBESITY AS A COMPLEX DISEASE
 Genetic variation, as captured by PRS
(„Polygenic Risk Score“) , not only influenced
birth weight, but also child size and adiposity up
to 48 months of age, independent of birth
weight.
 The PRS was constructed using adiposity-linked
genetic risk variants previously reported in an
adult population. The association of adult
adiposity risk score with size and adiposity in
pediatric population indicates that the effects of
genetic risk variants can be detected as early as
birth.
OBESITY AS A COMPLEX DISEASE (BMC MED. 2017; 15: 50)
 Neonatal methylation levels at seven loci were associated with birth
weight. At six of the seven loci, there was suggestive evidence that the
associations continued to persist up to 48 months of age. Among them,
two of the loci (CDKN2B/P4HA3) also showed suggestive association with
child BMI at 48 months. Even though the associations in early childhood
did not survive multiple testing corrections, these CpGs still hold potential
as biomarkers of adverse metabolic trajectory as the prevalence of
obesity increases with age and might become more apparent later in
the life-course. Lastly, methylation levels at three of seven loci associated
with birth weight (IGDCC4, MIRLET7BHG, CACNA1G) also showed
significant associations with the prenatal environment; however, similar
analyses with childhood weight and adiposity measures showed
suggestive associations.
 Birth weight seems to be influenced by both genetic and prenatal
environment factors, possibly acting through different mechanisms, either
by altering the epigenome (evidenced by CpGs that were associated
with prenatal environment and/or SNPs) or independently of the
epigenome (e.g. the PRS).
ANOREXIA NERVOSA (AN)
AND BULIMIA NERVOSA (BN)
 are complex psychiatric disorders of great
importance for public health policies, as
they are associated with a high burden of
morbidity and mortality due to their severe
medical and psychological consequences.
Etiopathogenesis of these eating disorders
(EDs) continues to remain elusive, with the
result that their treatment is often
unsuccessful.
 AN is a severe psychiatric disorder leading to
life-threatening weight and fat loss. This
illness could be characterized by irrational
fear of becoming fat, abnormal eating
behavior, hyperactivity, GIT complications
and wide variety alterations of hormonal
and metabolic systems.
 The exact etiopathogenesis is unknown and
the way of treatment remain limited.
Schematic representation of brain reward circuits.
ACC anterior cingulated cortex; Amy amygdala; DS dorsal striatum; Hipp
hippocampus; IC insular cortex; LH lateral hypothalamus; mPFC medial
prefrontal cortex; NAc nucleus accumbens; OFC orbitofrontal cortex; VTA
ventral tegmental area.
The brain reward system integrates basic
and emotional stimuli, such as hunger,
satiety, desire, pleasure and fear, with
higher order cognitive processes aimed at
modulating further actions or
representation of the general experience.
These high order processes involve
anterior cingulate cortex (ACC),
orbitofrontal cortex (OFC) and
ventromedial prefrontal cortex (PFC),
which are necessary for identification of
rewarding stimuli, inhibition of emotional
responses, and promote behavioral
outcomes (Haber and Knutson, 2010;
Wittman et al., 2010 ; Sripada et al.,
2011). Overall, the PFC provides
inhibitory influences on motivation and
reward-directed behavior, integrating
sensory inputs, memories, goals, and
physiological states with the aim to
provide an adequate performance (Miller
and Cohen, 2001). ACC and dorsolateral
prefrontal cortex (DLPFC) may also serve
to monitor potential conflict situations
induced by reward stimuli (Walton et al.,
2003 ; Vogt et al., 2005). Therefore, they
have a gating role in action selection
following reward cues ( Goldstein and
Volkow, 2011). Indeed, by a top-down
effect, both OFC and ACC provide a
negative feedback to mesolimbic areas
regulating reward-seeking motivation
(Goldstein and Volkow, 2011).
ANOREXIA NERVOSA (AN) AND BULIMIA
NERVOSA (BN)
 Functional magnetic resonance imaging (fMRI) techniques have
been employed to investigate the brain's processing of reward
elicited by both food-related and non-food-related stimuli in AN
and BN (O'Hara et al., 2015).
 It has been shown that, compared to healthy controls, AN
patients exhibit abnormal activation of different brain areas,
including the parietal, the orbito-frontal, the dorso-lateral
prefrontal, the anterior cingulate and the medial prefrontal cortex
(Frank, 2015a ; Frank, 2015b) after exposure to visual food cues,
especially for highly palatable foods.
 Similarly, altered insula, striatum or orbitofrontal responses to sweet
stimuli have been found in recovered or symptomatic AN and BN
patients.
 These findings suggest a dysregulation of brain mechanisms
involved in the processing of food-related rewarding stimuli in the
pathophysiology of EDs.
PATHOPHYSIOLOGY OF AN
 An integral pathophysiological scenario that fits to the natural
history of AN with the following steps an be porposed:
 (1) enhanced vulnerability to stress (genetic, epigenetic, or
environmental factors);
 (2) major stressing events activating the stress-axis, increased
intestinal permeability, and increased virulence of the microbiota;
 (3) bacterial proteins (e.g., ClpB) challenge the immune response
and due to molecular mimicry, cause increased production of Igs
cross-reactive with neuropeptides (e.g., α-MSH);
 (4) this results in altered food intake, anxiety, gastrointestinal
discomfort and other consequences of altered central and
peripheral melanocortin signaling;
 (5) global malnutrition and some specific macro- and micronutrient
deficiencies contribute to the perpetuation of gut barrier
and immune dysfunction as well as behavioral symptoms.
Front Neurosci. 2016; 10: 256
OREXIGENIC NEUROPEPTIDES
 Orexigenic neuropeptides including ghrelin, orexins
and 26RFa are up-regulated in AN and it is thought
that this orexigenic profile reflects an adaptive
mechanism of the organism to promote food intake
and thus to counteract undernutrition. However, this
adaptive mechanism is ineffective in increasing food
consumption leading to the concept of a global
resistance of AN patients to orexigenic signals.
 We can speculate that a chronic increase of the
activity of LHA orexigenic neurons expressing orexins,
MCH, or 26RFa could reinforce dopamine-induced
anxiety in the reward system of AN patients and thus
the aversion to ingest food.
Front Neurosci. 2016; 10: 256
Front Neurosci. 2016; 10: 256
LOSS OD ADIPOSE TISSUE IS SUPPOSED TO BE THE MAIN
FACTOR CONTRIBUTING TO THE BODY WEIGHT LOSS
NW (n = 50) AN (n = 30)
Weight (kg) 62.2 ± 1.54 45.8 ± 1.89*
Lean mass (kg) 39.1 ± 0.76 37.8 ± 1.01
BMI (kg/m2) 21.2 ± 0.42 15.7 ± 0.47*
Body fat content (%) 24.3 ± 0.79 7.1 ± 0.88*
Total fat skinfold (mm) 120.5  12.17 42.1  4.78*
Abdominal skinfold (mm) 12.5  2.13 4.8 ± 1.59*
Insulin (pmol/l) 28.3 ± 4.53 14.2 ± 3.67*
Glucose (mmol/l) 4.7 ± 0.08 4.1 ± 0.11
Menstruation Yes - regular cycle Secondary amenorrhea
Means ± SEM
 AN is 11x more frequent in
relatives of probands compared
to physiological population.
 BN is 4-5x more frequent in relative
women.
 ~15% risk of eating disorders in
relatives of AN and BN vs. 4% risk in
healthy population.
Strober et al. Am J Psychiatry 2000; 157:393
GENETIC ASSOCIATIONS???
DĚKUJI VÁM ZA POZORNOST