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 a normal range is arbitrary to a 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 one of many symptoms in some diseases – especially of endocrine
ones, e.g.
• hypothyroidism
• Cushing syndrome
• hypogonadism
• however, the 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)
• the 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
• the 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)
• isotopes
Adipocyte = cell specialised to acummulate lipids
• function of adipocytes
• mechanical support / protection
• thermoinsulation
• energy store
• endocrine organ (~1109 of cells = by far the largest!!!)
• insulin-sensitizing factors (negatively correlating with the number of adipocytes)
• few adipocytes = muscle has to be very insulin sensitive in order to utilize Glc?
• insulin-desensitizing factors (positively correlating with the 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 the 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)
• the interaction exists even within organs
• e.g. liver: hepatocytes/adipocytes/Kuppfer cells
• two periodically changing situations required the 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 (intra-abdominal) fat tissue
• localization
• omentum, mesenterium, retroperitoneum
• visceral adipocytes are different from s.c. !!!!
• lower LPL activity
• higher HSL activity compared to subcutaneous fat
• 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 the to lipolytic
effect of catecholamines and GC, lower
sensitivity the to anti-lipolytic 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 =
dyslipidaemia
• 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 both, but more in v.
• however, results of studies are controversial (acute
vs. long-term, animal vs. humane, the contribution of
hyperinsulinemia, …)
• (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
• interindividual variability in the capacity of
differentiation (genetics?)
Hypertrophic, overloaded adipocyte
• overloaded adipocytes secrete cytokines attracting
monocytes
• hypoxia (HIF-1)
• ER stress
•  leptin/adiponectin ratio (i.e. pro-/ anti-inflammatory
signaling)
• 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 or AD) or acquired
• generalized
• localized
• similar to metabolic syndrome
• dyslipidaemia
• 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, dyslipidaemia) 
atherosclerosis
• tumors
• ovary
• endometrial
• breast
• colorectal
• kidney cancers
• musculoskeletal system
• arthrosis of lower limb joints
• infertility
• polycystic ovary syndrome
• biliary calculosis (all bladder stones)
• respiratory insufficiency (morbid obesity – Pickwick syndrome)
• sleep apnoea
Etiopathogenesis 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 how to lose weight by diet after once gaining it
• but why this is possible?
• is there any feedback loop between adipose tissue and central and
peripheral organs influencing metabolism and food intake in order to
prevent the increase of body weight over the threshold necessary for
the optimal functioning of an organism? ENERGY HOMEOSTASIS????
Energetic homeostasis of the single 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 protein synthesis
•  lipolysis and lipogenesis in adipocytes
•  synthesis of TAG and de novo lipogenesis
• the activity of AMPK is regulated by
• „upstream“ kinases (e.g. calmodulin-dependent k. or LKB1)
• adipokines (adiponectin, leptin)
• pharmacologically (metformin)
That is why metformin is a first-line antidiabetic
drug (insulin-sensitiser)
• Metformin acts primarily to suppress glucose production
in the liver. While metformin's mechanism(s) of action
remain controversial, current evidence indicates that
metformin's most important effect in treating diabetes
is to lower the hepatic production of glucose (as
summarized in the top left box).
• Current evidence suggests that results from a
combination of intracellular effects in the liver.
When metformin is taken orally, it is absorbed into
hepatocytes from the portal vein through plasma
membrane transporters, including the organic cation
transporter 1 (OCT1).
• Inside the cell metformin inhibits mitochondrial
respiratory-chain complex 1, resulting in reduced ATP
levels and increased AMP. Increased AMP levels
activate Adenosine Monophosphate-Activated
Protein Kinase (AMPK), which contributes to the
lowering of glucose production by at least 2 pathways:
• i) increased AMPK phosphorylates CBP & CRTC2
transcription factors, which inhibits genes involved in
the production of glucose (“gluconeogenic genes”);
• ii) increased AMPK also inhibits mitochondrial glycerol-
3-phosphate dehydrogenase (mGPD), leading to an
increase in cytosolic NADH, which both stimulates the
conversion of pyruvate to lactate, and simultaneously
decreases gluconeogenesis. An accumulation of lactate
to dangerous levels (lactic acidosis) can occur when
metformin is taken by patients with other conditions
resulting in metabolic acidosis (liver disease, heart
failure, sepsis, alcohol abuse), or kidney disease (as
indicated by elevated creatinine levels) because
metformin is eliminated by renal excretion) (He &
Wondisford, 2015; Nolte Kennedy & Masharani, 2015).
Pathogenesis of obesity
• endogenous and exogenous factors likely
contribute equally:
• endogenous
• genetic
• REE – measured by indirect calorimetry (RQ)
• foetal 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
• the 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 genetic predisposition plays probably an
important role it isn’t genes that would change rapidly
recently!
„thrifty“ genotype/phenotype
appetite
hedonistic regulation
diet
other factors
intake
GENETICS
intake/expenditure
ENERGIE
negative feedback
 energy
centrum in CNS
(hypothalamus)
leptin resistance??
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
• insulin receptor signalling cascade
• post-receptor sensitivity
• thermogenesis
• uncoupling proteins
• genome-wide association studies (GWAS)
– search for genes without a priori
hypothesis/known pathophysiological role
• FTO (fat-mass and obesity-associated) –
hypothalamic food intake regulation
• MCR4 (melanocortin receptor) - anorexigenic
• tens of others
• next generation sequencing
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
saccharides ( 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 microbiome vs. obesity
• 1014 microorganisms in the 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 in body weight
• germ-free animals have 40 lower body weight despite comparable food intake
in conventional animals
• following bacterial colonization 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 a shift of the microflora composition
• Firmicutes  Bacteroides
• apart from the effect of diet, the composition of gut microflora shows
significant similarity in families (twins, siblings, mother-offspring pairs)
• putative pathogenic mechanisms of bact. gut colonization contribution to
changes in body weight
• the variable energetic yield of the food
• low-grade endotoxemia
• 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 the timing of meals are
• appetite respectively hunger
• appetite = natural desire to eat which changes behaviour in order to get access to food
• hunger = feeling of the 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, and type of processing is influenced by various
exogenous and endogenous factors
• social, psychogenic, emotional, habitual, daily regimen, cost, season etc.
• regardless of these short-term physiological fluctuations energy balance should be balanced
in a 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 information
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 (cholecystokinin (CCK),
glucagon-like peptide 1 (GLP-1) and peptide YY)
• ghrelin – a hormone released from the stomach whose concentration rises during
fasting („hunger mediator“)
• the concentration of leptin (and indirectly of insulin) is proportional to the adipose
tissue mass and the 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 signalization – changes of insulinemia after a meal containing sugar
(„glycemic index) and proteins, dietary lipids influence insulinemia and thus satiety
minimally
• central integration of signals takes place in the 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 centers in the hypothalamus are not entirely
known yet but they evidently involve a complex cooperation network among
various CNS regions which influence behavior 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
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
• the central hormone in the regulation
of energy homeostasis and food
intake (thermogenesis?)
• central and peripheral action
• obesity is associated with
hyperleptinemia
• leptin resistance??? (parallel to
insulin resistance) is hypothesized to
play a role in the pathogenesis of
obesity
• endogenous highly set “adipostate”
might be also a problem of relapses in
obese subjects after losing 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 endocannabinoids binding to
CB1 and 2 receptors
• anandamide (arachidonoylethanolamid, AEA)
• 2-arachidonoylglycerol (2-AG)
• basal ganglia (n. accumbens and pallidum)
• prefrontal cortex
• homeostatic and hedonistic regulations are
largely independent
• therefore, unfortunately, the type and amount of
meal very often do not correspond with metabolic
needs
Retrograde signaling by EC
• The endocannabinoids (EC) anandamide and 2-AG
are synthesized in postsynaptic target cells such
as hippocampal pyramidal cells (right). Synthesis
is initiated by calcium influx through voltagegated
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 …