Food intake disorders - part I:
Pathophysiology of obesity, insulin
resistance, concept of metabolic syndrome
Body weight
Adipose tissue
Regulation of food intake
Adipokines
Overweight/obesity
Metabolic syndrome
Body weight
• adipose tissue
• males ~10–20% of body weight
• females 20–30% of body weight
• body weight increases with age in both genders
• it is a continuous trait, establishing normal range is arbitrary to certain
extent
• ideal weight is associated with the longest life- expectancy
• body weight is viewed also in the cultural, geographical and historical context
• obesity is a one of many symptoms in some diseases – especially
endocrinopathies
• hypothyreosis
• Cushing syndrome
• hypogonadism
• however, majority of obese subjects are
affected by “common” obesity of multifactorial
origin
Measurement of body weight & body composition
• BMI (body mass index)
• malnutrition BMI 18.5
• normal weight 20 – 24.9
• overweight 25 – 29.9
• obesity BMI 30 (mild 30 – 34.9, moderate 35 - 40, morbid 40)
• BMI unfortunately doesn’t indicate the distribution of fat = android (male
pattern, apple) and gynoid (female pattern, pear)
• male pattern has more health-risks
• fat distribution is more precisely reflected in WHR index (waisthip
ratio)
• nowadays it’s common to measure just waist circumference
• females: mild risk > 80 cm, high risk > 88 cm
• males >94 and >102 cm, respectively
• thickness of skin fold
• exact measurement of body fat content
• underwater weighing
• conductance (bioimpedance)
• computer tomography and magnetic resonance
• DEXA (dual energy X-ray absorptiometry)
• izotopes
Adipocyte = cell specialised to acummulate lipids
• function of adipocytes
• mechanical support / protection
• thermoisolation
• energy store
• endocrine organ (~1109 of cells = by far the largest!!!)
• insulin-sensitising factors (negatively correlating with number of adipocytes)
• few adipocytes = muscle has to be very insulin sensitive in order to utilize Glc?
• insulin-desensitising factors (positively correlating with number of adipocytes)
• when NEFA plentiful utilization of Glc in the muscle does not need to be efficient?
• pro-inflammatory factors (cytokines)  low-grade inflammation
Formation and utilization of lipid stores
Evolution of obesity and inflammation
• ability to store energy for periodical fasting was equally
important as an ability to fight infection
• biologically interconnected systems for energy storage and immune
reaction developed
• single system in lower organisms (e.g. fat body in insects)
• separate systems in higher organisms (liver, adipose tissue, bone marrow), but
dynamic cooperation
• hormones of adipose tissue and nutrients regulate immunity (e.g. via Toll-like
receptors)
• interaction exist even within organs
• e.g. liver: hepatocytes/adipocytes/Kuppfer cells
• two periodically changing situations required redistribution of
energy
• fasting (or danger)  stress reaction  decline of immunity
•  glucocorticoids /  lymphocytes
• storage of energy production of humoral factors in fat tissue with
pro-inflammatory effect  removal of pathogens
Fat distribution
• “brown” adipose tissue (BAT) –
newborns
• neck, back, around large vessels =
thermoregulation
• mitochondrial “uncoupling” of oxidation of FFA
and ATP synthesis
• “white” (WAT) stored at
• subcutaneous adipose tissue
• aesthetic but not metabolic catastrophe
• visceral adipose tissue
• intra-abdominally – e.g. omentum,
mesenterium
• retroperitoneally
• others
• epicardium
• local source of FFA?
• possible paracrine effect of secreted factors on
the heart
• orbital, joints, synovia
• ectopic intra-organ in muscles and liver
• two important organs influencing insulin
sensitivity
•  NEFA
•  adipokines
CHARACTERISTICS OF DIFFERENT
TYPES OF ADIPOSE TISSUE
(1) Brown adipose tissue (BAT)
WAT BAT
function energy storage production of heat
morphology single droplet of triglycerides,
variable amount of
mitochondria
multiple droplets of
triglycerides, large amount of
mitochondria
typ. protein leptin UCP-1
origin Myf5-negat. progenitor. cells Myf5-posit. progenitor. cells
humans  mass associated with health
risks
 mass associated with benefits
during the life  mass  mass
• well known role in non-shiver thermogenesis in newborns and
small mammals
• but adults have still some metabolically active BAT!
• dispersed in white adipose tissue
• initial mass and ability to differentiate new BAT can influence
interindividual predisposition to obesity or metabolic syndrome
• genetics?
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Differentiation of BAT (compared to WAT)
• common precursor of muscle cells and BAT
(Myf5+)
• + PRDM16  BAT
• in classical localizations (Myf5+ BAT)
• - PRDM16  muscles
• BAT also dispersed in WAT (Myf5-)
• trans-differentiation from WAT???
(2) White adipose tissue (WAT)
• (a) subcutaneous adipose
tissue
• aesthetic but not metabolic
catastrophe
• (b) visceral adipose tissue
• intra-abdominally – e.g.
omentum, mesenterium
• retroperitoneally
• (c) others
• epicardium
• local source of FFA?
• possible paracrine effect of
secreted factors on the heart
• orbital, joints, synovia
(2b) Visceral (intraabdominal) fat tissue
• localization
• omentum, mesenterium, retroperitoneum
• visceral adipocytes are different from s.c. !!!!
• lower LPL activity
• higher HSL activity než subkutánní tuk
• higher 11HSD1 activity = higher local production of
cortisol
• different density of receptors for GC, 3 adr., Ins, …
• lower leptin synthesis, higher production of prodiabetogenic
adipokines (e.g. resistin and RBP)
• in summary: higher sensitivity to lipolytic
effect of catecholamines and GC, lower
sensitivity to antilipolytic effect of insulin
and higher tendency to GC-stimulated
differentiation of adipocytes
• drained by v. portae = direct effect on liver
• glycerol is a substrate for gluconeogenesis =
diabetes/IGT/IFG
• esterification and synthesis of VLDL = dyslipidemia
• induction of hepatic lipase - -> modification of LDL
and HDL to small dense particles = atherogenesis
Ratio of SC and V fat tissue
• CT cross-sectional abdominal areas at umbilicus level in two
patients demonstrating variation in fat distribution
• A: Visceral type (49-yr-old female, 23.1 of BMI, visceral fat area:
146 cm2; subcutaneous fat area, 115 cm2; V/S ratio, 1.27)
• B: Subcutaneous type (40-yr-old female, 24.0 of BMI, visceral fat
area: 60 cm2; subcutaneous fat area, 190 cm2; V/S ratio, 0.31)
• cut-off of metabolic a CV risk >0.4
Cushing syndrome as an example of redistribution of s.c.
into visceral
• (1) regional differences in intensity of
lipogenesis vs. lipolysis between s.c. and
v. adipose tissue
• suppression of LPL in s.c.
• activation of ATGL/HSL in bot, but more in v.
• however results of studies are controversial (acute
vs. long-term, animal vs. humane, contribution of
hypeinsulinemia, …)
• (2) preferential differentiation of v.
adipocytes
• higher availability of cortisol due to  activity of
11HSD1
• (3) lower central effect on the control of
appetite
• end-result is central obesity with all the
components of metabolic syndrome
(2a) WAT - adipocyte differentiation
• in positive energy balance fat tissue does not expand passively = regulation of
adipocyte differentiation
• pluripotent mesenchymal cell (MSC)  adipoblast  pre-adipocyte  adipocyte
• control (transcription factors)
• peroxisome proliferator-activated receptor  (PPAR)
• expressed mainly in fat tissue
• stimulates adipocyte differentiation, lipogenesis and fat storage
• CCAAT regulatory enhancer binding protein  (CREBP)
• sterol-regulatory element binding protein 1c (SREBP1c)
• others (Wnt signalling pathway)
• hyperplastic but small adipocytes store
fat relatively “safely”
• „lipid overflow“ or „reduced adipose
expandability“ hypothesis of obesity
• limited differentiation plasticity of adipose
tissue (mainly subcutaneous) leads to
hypertrophy of existing adipocytes
• interinidividual variability in the capacity of
differentiation (genetics?)
Hypertrofic, overloaded adipocyte
• overloaded adipocytes secrete cytokines attracting
monocytes
• hypoxia (HIF-1)
• ER stress
•  ration leptin/adiponektin (i.e. pro-/ anti-inflammatory
signalisation)
• upon their differentiation into macrophages further
production of pro-inflammatory cytokines affecting
insulin sensitivity
• competition of Tyr- and Ser/Thr-kinases (signalization of
TNF-a vs. insulin for IRS-1)
• “low-grade inflammation”
• responsible for the development of co-morbidities
associated with obesity, esp. T2DM, atherosclerosis,
carcinogenesis, …
(3) Ectopic fat
• upon reaching maximum of saturation of WAT additional
nutrients are „redirected“ towards other organs not specialized
for storage of lipids, therefore sensitive to lipotoxicity
• inability to store unlimited amount of nutrients and limited
expandability of subcutaneous a. tissue leads to progressive
inflammation and production of pro-inflammatory adipokines
• apoptosis of hypertrophic adipocytes
• saturation of visceral fat
• NEFA “spillover”
• interferes with utilization of glucose in muscle ( ins. sensitivity)
• ectopic storage of fat in organs
• skeletal muscle
• insulin resistance
• myocardium
• cardiomyopathies
• arrhythmias
• apoptosis
• systolic dysfunction
• liver
• NAFLD/NASH
• pancreas (B-cells)
• apoptosis
Lipodystrophy as an extreme example of dysfunctional
subcutaneous fat tissue with metabolic consequences
• inherited (AR i AD) or acquired
• generalized
• localized
• similar to metabolic syndrome
• dyslipidemia
• hypertriglyceridemia and
hypercholesterolemia, low HDL
• impaired Glc tolerance
• visceral obesity
• liver steatosis
• …
Obesity
Overweight / obesity
• defined as an excessive deposition of fat in the body with
concurrent hyperplasia and hypertrophy of adipose tissue
•  differentiation of pre-adipocytes
•  deposition of lipids in adipocytes
• obesity is, first of all, consequence of abnormal long-term
regulation of energy homeostasis
• risks connected with obesity
• cardiovascular
• metabolic syndrome (diabetes, hypertension, dyslipidemia) 
atherosclerosis
• tumors
• ovary
• endometrial
• breast
• colorectal
• kidney cancers
• musculoskeletal system
• arthrosis of lower limb joints
• infertility
• polycystic ovary syndrome
• biliary calculosis
• respiratory insufficiency (morbid obesity – Pickwick syndrome)
• sleep apnoea
Ethiopathogenesis of obesity
• obesity develops as a consequence of long-term positive energy
balance, i.e. imbalance between
•  energy intake
• theoretically
• young healthy physically working man requiring 14 000kJ
• older sedentary woman 7 000kJ
• in reality
• average consumption 10 - 12 000kJ
•  energy expenditure
• combination of both
• however, there is no “static” state in vivo
(i.e. energy storage = energy intake – energy
expenditure) but “dynamic” because decreased intake decreases
resting energy expenditure (REE)
• creates a problem to loose weight by diet after once gaining it
• but why this is possible?
• is there any feed-back loop between adipose tissue and central and
peripheral organs influencing metabolism and food intake in order to
prevent increase of body weight over the threshold necessary for
optimal functioning of organism?
Energetic homeostasis of the cell
• 5' AMP-activated protein kinase (AMPK) expressed in most
energetically relevant organs, e.g. liver, muscle and brain
• activation of AMPK during energy depletion (AMP/ATP ratio)
• activation of catabolic pathways
•  liver FFA oxidation and ketogenesis
•  muscle FFA oxidation and transport of GLc
• inhibition of anabolic pathways
•  liver synthesis of CH and proteosynthesis
•  lipolysis and lipogenesis in adipocytes
•  synthesis of TAG and de novo lipogenesis
• activitz of AMPK regulated by
• „upstream“ kinases (e.g. calmodulin-dependent k. or LKB1)
• adipokines (adiponectin, leptin)
• pharmacologically (metformin)
Pathogenesis of obesity
• endogenous and exogenous factors likely
contribute equally:
• endogenous
• genetic
• REE – measured by indirect calorimetry (RQ)
• fetal programing
• exogenous
• physical activity
• exercise energy expenditure
• non-exercise activity thermogenesis (daily chores,
posture, fidgeting)
• diet (amount, frequency, quality),,
• others
• education, social class, psychological factors
(personality), stress
• recent change of behavioral and
environmental (not genetic!) factors is
responsible for the current epidemic of
obesity in developed countries (and its
growing prevalence in developing ones)
• although generic predisposition plays probably
and important role it isn’t genes that would
change rapidly recently!
„thrifty“ genotype/phenotype
apetite
hedonistic regulation
diet
other factors
intake
GENETICS
intake/expenditure
ENERGIE
negative feedback
 energy
centrum in CNS
(hypothalamus)
leptin resistence??
Genetics of obesity
• heritability of body weight 60
• methods
• association case-control studies with candidate genes = genetic polymorphism in
genes encoding products involved in
• regulation appetite/satiety
• peripheral and central orexigenic / anorexigenic mediators
and their receptors
• endocannabinoid system
• adipose tissue differentiation and metabolism
• PPARs, enzymes, adipokines and their receptors
• carbohydrate metabolism
• inzulin receptor signal cascade
• post-receptor sensitivity
• thermogenesis
• uncoupling proteins
• genome-wide association studies (GWAS) – search for genes without known
pathophysiological role
• FTO (fat-mass and obesity-associated) – hypothalamic food intake regulation
• MCR4 (melanocortin receptor) - anorexigenic
• tens of others
Environmental factors
• lack of physical activity
• change of diet
• lipid-rich diet brings twice as much energy in
the same amount compared to carbohydrates
and proteins
• lipids mediate the satiety much later than
sacharides ( insulin)
• national cuisine traditions
• family habits
• educational and social status
• consumption of alcohol can play a role too
• non-negligible energy content
• gut microflora
Gut microflora vs. obesity
• 1014 microorganisms in intestine (1000 species), 60 of stool volume
represent bacteria
• G+ Firmicutes 60
• Lactobcillus, Mycoplasma, Clostridium, …
• G+Actinobacteria 10
• G- Bacteroides 10
• others
• experimental findings support the role of gut microflora for body weight
• germ-free animals have 40 lower body weight despite comparable food intake
in conventional animals
• following bacterial colonisation of the energetic yield of the food, body weight
and hepatic lipid production is increased, conversely, insulin sensitivity is
decreased
• obesity, resp. high calorie food intake (i.e. high fat/high sugar Western
diet) is associated with shift of the microflora composition
• Firmicutes  Bacteroides
• apart the effect of diet, composition of gut microflora shows significant
similarity in families (twins, siblings, mother-offspring pairs)
• putative pathogenic mechanisms of bact. gut colonisation contribution to
changes of body weight
• variable energetic yield of the food
• low-grade endotoxinemia
• LPS  CD14 (TLR-4)  Kupffer cells  metabolic consequences in liver
• altered secretion of intestinal paracrine hormones (peptides) by enteroendocrine
cells
• slowing down intestinal motility and allowing thorough digestion and absorption
Other less common causes of obesity/hyperphagia
• tumors and lesions of
ventromedial hypothalamus
• mostly craniopharyngeoma
• monogenic genetic
syndromes
• Prader-Willi syndrome
• deletion or alteration of expression
of group of genes on the proximal
part of long arm of paternal
chromosome 15
• abnormally increased appetite
(hyperphagia) and subsequent
morbid obesity, muscular
hypotonia, mental retardation,
low height, hypogonadism and
acromicria (small hands and feet)
• high levels of ghrelin are common in
PW patients - consequence of
primary genetic defect?
REGULATION OF FOOD INTAKE
Food intake is a periodical event
• main stimuli regulating timing of meals are
• appetite respectively hunger
• appetite = natural desire to eat which changes behavior in order to get access to food
• hunger = feeling of imperative need of food associated with various objective symptoms, esp. negatively perceived
stomach contractions
• satiety
• satiety = opposite of hunger, follows after adequate meal
• frequency of meals, portion size, quality, type of processing is influenced by various exogenous
and endogenous factors
• social, psychogenic, emotional, habitual, daily regimen, cost, season etc.
• regardless these short-term physiological fluctuations energy balance should be balanced in
healthy man in long-term so that energy intake equals expenditure
• however, the regulation of food intake (and body weight) is not purely homeostatic but quite a
complex process involving neural and hormonal regulation
• (A) homeostatic regulation
• afferent signals are so far much better understood than efferent signals
• (B) hedonistic regulation
• satisfaction after meal
(A) Homeostatic regulation
• afferent signals (= appetite vs. satiety):
• peripheral signals via systemic humoral factors and
sensitive iformation from GIT informing about gastric
distension and motility (via n. vagus and n. tractus solitarii)
• the most important humoral factors are:
• insulin – postprandial release paralleling the glycemia
• leptin – adipose tissue hormone, likely involved in long term
modulation of sensitivity to peripheral “satiety” signals from GIT
(cholecystokinine (CCK), glucagon-like peptide 1
(GLP-1) and peptide YY)
• ghrelin - hormone released from stomach whose concentration rises
during fasting („hunger mediator“)
• concentration of leptin (and indirectly of insulin) is proportional to
the adipose tissue mass and intensity of their signals in CNS (via
their receptors) is related to their plasma levels
• meal composition (amount of carbohydrates, proteins and lipids)
is reflected in afferent signalisation – changes of insulinemia after
meal containing sugar („glycemic index) and proteins, dietary
lipids influence insulinemia and thus satiety minimally
• central integration of signals takes place in hypothalamus
(hypothalamic nuclei – nucleus arcuatus) by local
neurotransmitters:
• orexigenic mediators (neurotransmitters)
• neuropeptide Y (NPY)
• agouti-related peptide (AgRP)
• anorexigenic mediators (neurotransmitters)
• proopiomelanocortine (POMC)
• cocaine-amphetamine-regulated transcript (CART)
• efferent signals
• events initiated by primary centres in hypothalamus are not
entirely known yet by they evidently involve complex
cooperation network aming various CNS regions which
influence behaviour in order to seek food
• secondary mediators
• orexigens - orexin A and B, galanin and norepinephrine
• anorexigens – melanocyte-stimulating hormone (-MSH),
corticoliberin (CRH), thyreotropin-releasing hormone (TRH) and
serotonin
Peripheral and central signalling in regulation of
food intake
syntéza
Leptin [“leptos” = lean]
• spontaneously obese strains of mouse
- mutations in Ob or Db genes
• Jackson laboratory (USA) from 1950
• identified by J. M. Friedman in 1994
• central hormone in regulation of
energy homeostasis and food intake
(thermogenesis?)
• central and peripheral action
• obesity is associated with
hyperleptinemia
• leptin resistance??? (parallel to
insulin resistance) is hypothesised to
play a role in the pathogenesis of
obesity
• endogenous highly set “adipostate”
might be also a problem of relapses in
obese subjects after loosing weight
Regulation of hypothal. centers by leptin
(B) Hedonistic regulation
• = sensations connected with meal (e.g.
palatability, vision, reward, ...)
• afferent signals
• gustatory and olfactory pathways into particular
centres
• cortical regions (prim. and associated centers)
• ventral tegmental area (VTA) – dopaminergic stimulation
• sub-cortical regions - limbic system (amygdala)
• they mediate the “good” feeling
• neuro-modulators are endocanabinoids binding to CB1
and 2 receptors
• anandemid (arachidonoylethanolamid, AEA)
• 2-arachidonoylglycerol (2-AG)
• basal ganglia (n. accumbens
and pallidum)
• prefrontal cortex
• homeostatic and hedonistic regulation are
largely independent
• therefore, unfortunately, the type and amount of
meal very often doesn’t corresponds with metabolic
needs
Retrograde signaling by EC
• The endocannabinoids (EC) anandamide and 2AG
are synthesized in postsynaptic target cells
such as hippocampal pyramidal cells (right).
Synthesis is initiated by calcium influx through
voltage-gated calcium channels, or by the
activation of G protein-coupled
neurotransmitter receptors, including type I
metabotropic glutamate receptors (mGluR) or
muscarinic acetylcholine receptors (mAChR)
• The EC gain access to the extracellular space
and activate CB1 cannabinoid receptors found
concentrated on certain nerve terminals, e.g.,
of cholecystokinin-containing GABAergic
interneurons in hippocampus
• CB1 activation causes presynaptic inhibition of
GABA or glutamate release by inhibiting
calcium channels, interfering with vesicle
release, and activating potassium channels
• The EC are taken up into postsynaptic or
presynaptic cells by the anandamide
transporter (AT). The degradative enzyme
FAAH is present in postsynaptic cells, and
monoglyceride lipase (not shown), which
degrades 2-AG, is found in presynaptic
terminals.
ADIPOSE TISSUE AS AN
ENDOCRINE ORGAN
Adipokines (vs. insulin sensitivity)
HORMONE TARGET
TISSUE/ORGAN
PLASMA LEVELS METABOLIC EFFECT
Leptin CNS
(hypothalamus),
muscle, ovary)
pozitive correlation
with BMI
central – long-term  of appetite and  of
sympathetic activity; peripheral -  insulin
sensitivity and lipid metabolism
Adiponectin insulin-dependent
tissues (muscle!)
negative correlation
with BMI
 of insulin sensitivity,  NEFA oxidation,
antiinflammatory
Resistin insulin-dependent
tissues (muscle!)
pozitive correlation
with BMI in rodents
 insulin resistance, pro-inflammatory
TNF- insulin-dependent
tissues (muscle!)
pozitive correlation
with BMI
interferes with insulin receptor signalling
(phosphorylation of serin residues) – 
insulin resistance
IL-6 ? pozitive correlation
with BMI
? (pro-inflammatory?)
Angiotensinogen adipose tissue
(para- and
autocrine action),
endocrine as a part
of systemic RAAS?
expression in
adipose tissue
positively correlates
with BMI
influence adipocyte differentiation, 
lipogenesis, circulatory effect of obesity ij
systemic circulation?
… others (omentin, visfatin, apelin, …)
• many adipokines interfere with insulin signaling
•on the receptor level
•post-receptor interference
CONSEQUENCES OF OBESITY –
METABOLIC SYNDROME
Summary
• unlimited storage of fat is not metabolically „safe“!!!
• as to why is not clear?
• critically limited energy resources in adverse living conditions were likely evolutionary much
more important factor than eventual consequences of affluence
• selection of “thrifty genotype” in the hunter-gather period enabled its carriers to make the most from
minimal resources and represented selective advantage
• the very same metabolic regulatory tools preventing us from life-threatening energy depletion form
basis of metabolic diseases nowadays
• esp. insulin and leptin resistance
• humoral products of adipose tissue actively participate in multiple regulations negatively
affecting
• carbohydrate and lipid metabolism
• vascular homeostasis and circulation
•  ICAM,  NO
• immunity
• some cytokines and RAF
• fibrinolysis
•  PAI-1
• reproduction
How technology changes us …