Neuroendocrine regulation of food intake: physiology and pathophysiology

1
Neuroendocrine regulation of food intake
physiology and pathophysiology

• Dr. Ivana Dostalova, Ph.D.
• 3rd Department of Medicine, 1st Faculty of
  Medicine, Charles University, Prague
• 13.3. 2009

2
Contents

• Physiology of neuroendocrine regulation of
  food intake
• central regulation of food intake hypothalamus,
  neurohormones
• short- and long-term peripheral regulation of
  satiation and energy balance
• - GIT hormones (ghrelin)
• - Adipose tissue hormones (leptin)
• - Pancreatic hormones (insulin)
• Pathophysiology
• anorexia nervosa
• Obesity
• Cancer anorexia

3
Our prehistorical progenitors clearly did not
have the opportunity to suffer either from
obesity or anorexia nervosa
Thrifty genes theory genes predisposing to
effective energy storage enabled to survive
during times of starvation, however they
predispose to obesity nowadays.
4
The progression of mankind development
2.5 milion of years
50 years
Adapted from R. Unger
5
Historical view of the regulation of food intake

• Lipostatic hypothesis (Kennedy 1953) adipose
  tissue produces specific lipostatic factor
• Glucostatic hypothesis (Mayer and Thomas 1967)
  fluctuations in glycaemia lead to
  stimulation/inhibition of food intake (regulating
  organs brain and the liver)
• Combination of above mentioned

6
The physiological regulation of food intake is a
complex homeostatic process that is regulated by
many endocrine and metabolic factors in a
combination with visual, olfactory, taste
sensation, emotions, memory and the life
conditions
7
The balance between energy intake and expenditure
is tightly regulated and body weight is stable
despite day-to-day food intake fluctuations......
..but when the border is overestimated the
balance is broken.
8
Interactions between emotions and
metabolic/endocrine regulations
Berthoud et al. 2006
9
Hypotalamic satiety centre (neuropeptides,
leptin, insulin)
Genetic background
Energy expenditure
Food intake
Sympathetic nervous system - Energy expenditure,
lipolysis
Life styl
Gastrointestinal tract ghrelin, peptide YY
Adipose tissue leptin, adiponectin, resistin,
TNF-a
10
Hypothalamus and brain stem are crucial in
central regulation of feedingIntegration of
brain neurotransmiters, peripheral neurohumoral
afferents, adipocyte-derived signals, GIT
peptides
Modulated by neocortex

• N. arcuatus (ARC) receptors for hormones and
  neuropetides that regulate feeding
• N. paraventricularis (PVN) integration of
  signals from ARC with thyroid and HPA axes
• N. vagus satiety signals to the brain stem
  after ingestion of a meal
• N. tractus solitarius PVN connection of
  brainstem with hypothalamus (serotoninergic
  neurons)

Source Morton et al. 2005
11
Hypothalamus

• Ventromedial nuclei satiety centre (lesion
  leads to hyperfagia)
• Lateral nuclei hunger centre (lesion leads to
  anorexia)
• N.arcuatus pivotal role in the integration of
  signals regulating appetite
• N. suprachiasmaticus timing (lesions in humans
  lead to night hyperfagia and obesity

12
Hypothalamic neuropeptides

• Stimulating food intake (orexigenic)
• Neuropeptide Y/ agouti-related protein (AgRP) in
  n. arcuatus
• Orexins/hypocretins
• Endocannabinoid system (treatment with opioid
  cannabinoid CB1 receptor antagonists
  anorexigenic effects)
• Galanin (depression GalR2- pharmacological
  treatment of depression and associated nutrition
  disturbances
• Beacon
• Inhibiting food intake (anorexigenic)
• POMC/CART
• a- MSH (cleavaged from POMC) MC4 receptors
• Serotonin
• BDNF
• CRH
• TRH
• Nesfatin-1 (stres, nálada, spánek, jídelní
  chování, úzkost, strach, regulace výstupního
  signálu z n. PVN)

13
Pleiotropic effects of hypothalamic neuropeptides
14
Systems situated in the brain act in peripheral
tissues due to variety of receptors and vice
versa Type and number of receptors is crucial
for specific effects of endocrine systems
ENDOCANNABINOID SYSTEM
15
Energy homeostasis is controlled by peripheral
signals from adipose tissue, pancreas, and the
GIT. Gut-derived peptides and adiposity signals
influence central circuits in the hypothalamus
and brain stem to produce a negative () or
positive () effect on energy balance. Thus the
drive to eat and energy expenditure are adjusted
so that over time, body weight remains stable.
16
Long-term adiposity signals (leptin) interact
with short-term satiation signals (CCK)

• hypothalamus-hindbrain projection
• Leptin and insulin acts in hypothalamus to
  enhance central sensitivity to short-term satiety
  signals (CCK)
• secretion of GLP-1 and CCK in intestine
• satiety signals are integrated with fat amount

Cummings and Overduin 2007
17
Factors regulating food intake
SATIETY FACTORS HUNGER FACTORS
Stomach and duodenum distension (n.vagus) Hungry contractions
heat cold
? glucose, amino acids, lipids in blood ? glucose, amino acids, lipids in blood
catecholamines orexins
serotonin endorphins
ACTH Galanin
Insulin (food in stomach) Glutamic acid
Leptin cortisol
CCK (lipids in duodenum) Neuropeptide Y
MSH GABA
glucagon ghrelin
Peptide YY AMPK
18
AMPK integrates nutrient and hormonal signals to
regulate food intake
In peripheral tissues
In hypothalamus
19
Peripheral signals involved in the regulation of
food intake

• Gastrointestinal hormones
• Pancreatic hormones
• Adipose tissue hormones
• Orexigenic (e.g., ghrelin)
• Anorexigenic (e.g., insulin, peptide YY, CCK,
  leptin)

20
Adipose tissue plays an important role in the
regulation of energy homeostasis
21
The role of adipose tissue in human body

• Adipose tissue constitutes about 20-30 of total
  body mass
• Source of energy (long-term starvation induces
  triglyceride breakdown to fatty acids and
  glycerol, both is further used as an energy
  source)
• Thermoregulatory function (thermic isolator)
• Mechanical protection of internal organs
• Endocrine function (control of food intake, lipid
  and carbohydrate metabolism)
• Accumulation of lipophyllic compounds (exogenous
  toxins)
• Conversion of prohormones to active hormones
  (increased local production of cortisol in
  visceral adipose tissue)
• Adipocyte capacity to differentiate and to store
  lipids is a principal determinant of protection
  against insulin resistance induced by ectopic fat
  storage

22
The size and endocrine profile of adipocytes
reflects obesity or leanness
Malnutrition (Anorexia nervosa)
Normal (sligthly overweight)
Obese
23
1994 adipose tissue can produce hormones
discovery of leptin
Leptin treatment of leptin-deficient ob/ob mice
normalized their body weight and recovered their
fertility
Mutation of ob gene encoding protein hormone
leptin produced by adipocytes results in morbid
obesity in mice
Zhang et al, Nature, 1994.
24
LEPTIN (167 AA, 16 kDa)

• Pleiotropic hormone/cytokine
• Regulation of fat mass - coordination of feeding
  behavior, metabolism, ANS a energy balance
• Neuroendocrine of food intake and energy
  expenditure (hypothalamus)
• reproduction, insulin sensitivity in liver and
  muscle (AMPK), immunoregulation, lipolysis
• Regulation hormonal (? inzulín, glukóza,
  glucocorticoids, estrogens, TNF-a x ?
  ß-adrenergic agonists), nutritional (fasting),
  amount of fat mass, receptor binding (plasma)
• Indicator of energy disbalance
• ? leptin adaptive response to fasting ? ?
  cortisol, ? thyroxin, gonadal hormones,
  thermogenesis, hyperfagia after fasting

25
Leptin acts in hypothalamusNeuroendocrine
control of food intake and energy expenditure
Flier 2004
26
Leptin can be supplied in activation of MC4R
Leptin-dependent melanocortin signaling in the
regulation of EE
Leptin-independent melanocortin signaling in the
regulation of EE
Shimizu et al. 2007
27
Leptin started the recognition of adipose tissue
as an endocrine organ..

• but it has continued

28
Adipose tissue produces numerous hormones and
cytokines
These factors are produced not only by
adipocytes, but also by macrophages, fibroblasts,
endothelial cells and other cells present in
adipose tissue
Adipose tissue- derived hormones 1.
Proinflammatory (TNF-?, IL-6, resistin) 2.
Anti-inflammatory (adiponectin) These hormones
markedly contribute to metabolic regulations
29
Products of adipose tissue
Adipocyte secreted cytokines (leptin,
adiponectin, visfatin, acylation stimulating
protein, metallothionein I, II, nerve growth
factor, haptoglobin
FFA, glycerol
Chemokines MCP-1, IL-8, Eotaxin, CCL-5
Stromovascular and adipocyte-secreted cytokines
IL-6, TNF-?, IL-1?
Growth factors FGF, TGF-?, CNTF, MCSF
Extracellular matrix proteins collagen type
III, fibronectin
Hemostatic factors PAI-1, Tissue factor
RAS components renin, angiotensinogen,
angiotensin I, II
Adhesion molecules VCAM-1, ICAM-1
Other factors resistin, RBP-4, vaspin, omentin,
apelin, prolactin
Enzymes lipoprotein lipase, adipsin, matrix
metalloproteinases
Angiogenic factors VEGF, HGF
30
Adiponectin

• Predominantly produced by adipocytes
• Circulates in 1000-times higher concetrations
  than other hormones
• Insulin-sensitizing, anti-atherogenic and
  antiinflammatory properties
• Regulates food intake (acts in hypothalamus)
• Most promising therapeutic properties among
  adipokines in the treatment of diabetes

31
How adiponectin increases food intake?
ADIPONECTIN
Hypothalamus n. arcuatus AdipoR1 receptor ?
Activity of AMPK
Dominant-negative AMPK expression in n.arcuatus
Stimulation of food intake
KUBOTA et al. 2007
32

• (?) Food
• intake

Adipocytes
Insulin sensitivity
Adiponectin
Endothelial cells
HB-EGF PDGF bFDF EGF
Proliferation migration
Cells of smooth muscle
Matsuda M. et al., JBC, 2002
33
Relationship between plasma adiponectin and body
mass index
34
Resistin

• in mice
• regulated nutritionally, prodiabetic properties
• produced predominantly by adipocytes
• x x x
• in humans
• nutritional regulation (?), effects in insulin
  sensitivity (?)
• produced predominantly by macrophages
• proinflammatory cytokine
• many isoforms in circulation problems with
  interpretation of data

35
Central administration of resistin promotes
short-term satiety in rats

• These effects are modest and transient
• Administration of resistin for several days did
  not affect body weight
• Resistin mRNA in n.arcuatus and ventromedial n.
  (brain-derived resistin acts in energy
  homeostasis?)
• Therapeutic and physiological effects probably
  limited

Tovar 2005
36
Direct effects of adipose tissue derived hormones
on the brain

• Leptin, adiponectin, resistin and others have
  receptors in CNS and are present in the
  interstitial fluid
• All of these hormones were found to regulate food
  intake

37
The next part of the feeding control story is the
gastrointestinal tract..

• Gastrointestinal hormones play an important
  role in the neuroendocrine regulation of food
  intake and postprandial satiety

Holst B, Schwartz TW. 2004
38
More than 40 gastrointestinal hormones discovered
to date
39
GIT and pancreatic peptides are anorexigenic
(satiety) vs. ghrelin is the only orexigen
(hunger)
Cummings and Overduin 2007
40
Satiation signals arise from multiple sites of GI
system stomach, proximal and distal small
intestine, colon, pancreas

• Ingested food evokes satiation by 2 primary
  effects on GIT
• Gastric distension
• Release of peptides from enteroendocrine cells
• Hindbrain the principial central site for
  short-term signals that are transmitted
• Neurally (n. vagal to n. tractus solitarius)
• Hormonally (gut peptides acting directly on area
  postrema outside of BBB)

Cummings and Overduin 2007
41
Intestinal satiety peptidesCholecystokinin

• I cells of duodenal and jejunal mucosa, brain,
  enteric nervous system
• Secreted in response to luminal nutrients
  (lipids, proteins)
• Decreases meal size in a dose-dependent manner
• Satiating effects
• Triggers the stereotyped sequence of eating
  behavior in rats
• Inhibition of gastric emptying
• Allelic variants of CCK associated with specific
  eating patterns (excessive portion size, extreme
  snacking behavior) were identified (De Krom 2007)

42
Intestinal satiety peptidesGlucagon-like peptide
1

• L cells of distal small intestine and colon
• Biphasic stimulation by ingested nutrients
  (lipids, carbohydrates)
• inhibits food intake and reduces body weight
• Modulator of the stress response related to taste
  aversion (contact with CRH in n.paraventricularis)
  
• Potent insulinotropic and glucagonostatic hormone
  (improves insulin release, attenuates glucagon
  release, improves glucose disposal)
• Ideal candidate for treating diabetes (GLP-1
  analoque exenatide)

43
Intestinal satiety peptides - Peptide YY

• Produced by distal intestinal L cells
• Physiological role in appetite by signaling the
  end of meal in n. arcuatus (inhibition of NPY)
• Slows gastric emptying and GI motility, inhibits
  secretion of gastric acid
• Increases shortly after a meal vs. fasting
  reduces its levels in healthy subjects
• Secreted postprandially in proportion to caloric
  load (L gt C gt P) in a biphasic manner (neural,
  nutrient)
• Beside short-term regulation of satiety involved
  in long-term regulation of energy expenditure and
  body weight

44
Similarities in nutrient-sensing mechanisms used
by taste-receptor cells of the tongue and
enteroendocrine cells of the intestine
(exemplified by an L cell).
45
GHRELIN (28 AA)
The only known peripheral orexigenic hormone

• Predominantly produced in the stomach (Kojima
  1999)
• Orexigenic and prokinetic effects
• Inverse relationship with leptin
• The regulator of postprandial satiety
  (physiological meal initiator)
• Dual action - short-term reg. of satiety and
  long-term reg. of body weight - low in obesity
  (postprandially) and high in AN (fasting)
• The product of the same gene as ghrelin
  obestatin (really orexigenic antagonist of
  ghrelin or the compensatory factor of ghrelin
  action?)

46
Ghrelin serves as a physiological meal initiator
in human
wide range of circulating ghrelin values between
two individuals and the heterogeneity of the
surge before breakfast
Cummings et al. 2001
47
Ghrelin acts in hypothalamus on NPY/AgRP and
POMC/CART reurons in an opposite manner to leptin
Rapid effects mediated by n. vagus
48
The secretion of ghrelin in stomach regulated by
the combination of mechanical, chemical, neural
and hormonal signals with unknown priority
Macronutrient composition (C gt P gt F) Osmolarity
in intestine Stomach and duodenum
distension Nervus vagus Insulin glucose
SST somatostatin, CCK cholecystokinin, GH
growth hormone Source Casanueva F, Diaguez C.
2004
49
Plasma obestatin decreased simultaneously with
ghrelin after mixed-meal in healthy women
Sedlackova et al. 2008
50
Possible clinical application of ghrelin

• GH deficiency
• Diagnosis of pituitary function
• Child and adult GH deficiency
• Eating disorder
• AN
• Bulimia nervosa
• Prader-Willi syndrome
• Gastrointestinal disease
• Cardiovascular disease
• Heart failure
• Dilated cardiomyopathy
• Osteoporosis
• Aging
• Catabolic state or chronic wasting syndrome
• Cachexia
• cancer, cardiac cachexia, AIDS, postoperative
  patients
• SourceKojima M, Kangawa K. 2005

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Pancreatic peptides regulating food intake

• Pancreatic polypeptide
• secretion stimulated postprandially in proportion
  to caloric load (under vagal control)
• Influences exocrine pancreatic function, GI
  motility, gastic acid secretion
• Peripheral administration reduces feeding vs.
  central a. increases feeding ???
• Amylin
• cosecreted with insulin postprandially by
  pancreatic beta cells
• Inhibits gastric emptying, gastric acid and
  glucagon secretion
• Decrease meal size and food intake
• Amylin analoque pramlintide diabetes treatment
• Insulin
• marker of adipose tissue mass
• Secretion in response to caloric influx (but not
  the meal initiator as ghrelin)
• Regulation of satiety and meal termination
• Potent signal for leptin secretion

52
OBESITY
53
Obesity is classified by Body Mass Index (BMI)
BMI
54
Waist circumference is a helping indicator of
visceral fat this fat is the most
metabolically active and thus the most harmful
55
Complications of obesity

• Mechanical joint illness, dyspnoe, sleeping
  apnoe, heart hypetrophy,..
• Metabolic - diabetes, hypertension,
  hyperlipoproteinemia, ischemic heart disease,
  ictus, tumours, sterility, depression,..
  Reaven metabolic syndrome

56
Patients characteristics
Lean controls
Overweight
I. and II. degree obesity
III. degree obesity
plt0,05 x vs. controls
57
Leptin gene mutation causes morbid obesity in
humans, but.
Farooqi SI, J. Clin. Invest. 1101093-1103 (2002)
58
Leptin and obesity

• Leptin deficiency is not epidemiologically
  significant cause of obesity (3 cases of
  leptin-gene mutation in humans accompanied by
  morbid obesity)
• Most of obese patients have hyperleptinemia i.e.
  circulating leptin levels correlate with body fat
  content
• Body weight loss induces decrease in circulating
  leptin levels
• Clinical trials focused on the treatment of
  obesity with leptin did not show significant
  benefit of leptin treatment to body weight loss

59
Why hyperleptinemia does not suppress food intake
in patients with obesity?

• Resistance to leptin effects either on the
  levels of leptin transport across the blood-brain
  barrier or on the postreceptor level
• Primary leptin function is not to suppress food
  intake, but to trigger complex adaptive reaction
  of human body to starvation.

60
Obesity is accompanied by local inflammatory
response in adipose tissue
61
Obesity leads to subclinical inflammation in
adipose tissue
Lean mice
Moderately obese mice
Morbidly obese mice
Strong positive correlation between adipocyte
size and the number of macrophages in adipose
tissue
Weisberg et al., JCI, 11217961808 (2003).
62
Obesity in mice is accompanied by decreased
adiponectin
Haluzik et al, 2003
63
Serum adiponectin concentrations and mRNA
expression of adiponectin and its receptors in
subcutaneous adipose tissue
Control
Overweight
I. and II. degree obesity
III. degree obesity
plt0.05 x vs. control
64
Correlation of serum adiponectin, subcutaneous
adiponectin mRNA and adiponectin receptors mRNA
expression with BMI
R - 0.46 Plt0.001
R -0.524Plt0.001
R - 0.354 P0.004
R - 0.076NS
65
Obesity and GIT hormones

• Decreased satiety perception represents an
  important risk factor for the development of
  obesity (Degado-Aros 2004)
• Alterations in hormonal responses to food intake
  contribute to decrease satiety in obese (Schwartz
  and Morton 2002)
• GIT hormones hot candidates on regulators of
  appetite and satiety in obese patients

66
Food fails to suppress ghrelin in obese
Postprandial ghrelin response in obese is (in
contrast to healthy subjects) independent of
caloric content and macronutrient composition of
a meal
Contribute to resistance to weight loss in some
of obese patients?
English et al. 2002
67
Fasting and postprandial levels of PYY, total
ghrelin, acylated ghrelin and CCK in lean, obese,
and morbidly obese
Total ghrelin
PYY
Active ghrelin
Triangle lean White square moderate
obese Black square morbidly obese
CCK
ZWIRSKA-KORCZALA et al. 2007
68
Why gastric bypass leads to substantial weight
loss as compared to bastric banding surgery?
OW obese controls BDN gastric banding RYGBP
gastric bypass
Korner et al. 2006
69
Obesity and pancreatic polypetide ?

• PP low in obese vs. normal in morbidly obese
• Obesity associated with impaired intestinal peak
  of PP postprandial response
• ? Importance in the pathophysiology of obesity
  (insulin resistance)

70
Peptide YY and obesity ?

• Fasting PYY low or normal in obesity
• Obese subjects exhibit normal sensitivity on
  PYY-induced anorexia
• PYY deficiency rather than PYY resistance may
  contribute to the pathogenesis of obesity
• Postprandially, PYY response blunted in obese
• Caloric load required to evoke the same response
  in obese as in lean was more than double
• Obese subjects may have weaker PYY-induced
  satiety signal for an equivalent meal
  contribute to reduce satiety of obese

71
Cholecystokinin in obesity ?

• Fasting CCK increased in obesity
• Postprandial response of CCK on mixed-meal normal
• Role of CCK in human obesity, especially in less
  sensitivity to satieting effect of meals and
  consequently the meal size consumed in one
  occasion, was not confirmed and remains rather
  speculative

72
Melanocortin receptors in obesity

• Genetic deletion of MC4R in mice and humans
  results in severe hyperphagic obesity (Coll 2004)
• MC4R mutations responsible for up to 5 of cases
  of severe childhood obesity and between 0.5 and
  2.5 of adult obesity (Hinney 2006)
• MC4R deficiency one of the most common single
  gene disorder (Alhabri 2007)
• Phenotypic features of MC4R deficiency include
  hyperphagia, increase in fat and lean mass,
  increase in bone mineral density (Farooqi 2003)

73
Examples of antiobesity agents in development
Bays 2004
74
More slim and more fit means more success and
beauty..
.. but sometimes this motto of modern
societies leads to death
75
Anorexia Nervosa (AN)

• Severe psychiatric disorder of unclear etiology
  associated with significant morbidity and
  mortality (Hsu 1996)
• Prevalence 0.3 of young girls, mortalty of
  6/decade (Dardeness 2007)
• Irrational fear of becoming fat even if patient
  is of normal or usually underweight
• Phobic response to food, abnormal eating
  behavior, hyperactivity, weakness, muscle aches,
  sleep disturbances, GIT complications, mood
  disturances, alterations of wide variety of
  hormonal and metabolic systems
• Combination of cultural-social, psychological,
  biological factors

76
Diagnostic criteria for AN

• Refusal to maintain body weight at or above a
  minimal normal weight for age and height (e.g.,
  weight loss leading to maintenance of body weight
  less than 85 of that expected or failure to
  make expected weight gain during period of
  growth, leading to body weight less than 85 of
  that expected).
• Intense fear of gaining weight or becoming fat,
  even thought underweight.
• Disturbance in the way in which ones body weight
  or shape is experienced, undue influence of body
  weight or shape on self-evaluation, or denial of
  the seriousness of the current low body weight.
• In postmenarcheal females, amenorrhea, i.e., the
  absence of at least three consecutive menstrual
  cycles.
• Specify type
• Restricting type
• Binge eating/purging type
• American Psychiatric Association
  Diagnostic and Statistical Manual of Disorders,
  DSM-Q, American Psychiatric Association,
  Washington, DC, 1994.

77
Guidelines for clinical treatment of AN

• Refeeding and weight restoration
• Institute pharmacologic therapy
• Continue therapy for at least 3 month
• Resumption of menstruation
• Normalization of caloric needs
• Remediation of physical complications
• Remission of pathological eating and body-image
  distortions
• Revealuate need for continuing pharmacologic
  therapy
• Source The management of eating disorders
  and obesity, edited by DJ Goldstein, MD, PhD,
  Humana Press Inc. 1999, Totowa, New Jersey.

78
Alterations of plasma hormonal and biochemical
parameters in AN

• ? LH (? response to GnRH)
• ? FSH?/ GH
• ? IGF-1
• TSH (but delayed response to TRH)
• ACTH
• ? reaction on CRH
• ?/ PRL
• ? response to TRH
• ?T4 ? T3 ?/ rT3 fT4 ? fT3
• ?/ serum cortisol (? suppression in
  dexamethasone test)
• ?Estradiol ? Estron ? progesterone
• ? Serotonin
• ? Insulin glucose C-peptide?
• ? Plasma leptin ? plasma ghrelin ? plasma
  resistin ? plasma adiponectin
• plasma EPI plasma NE plasma glycerol
  plasma NEFA
• Source Nedvidkova et al. 2003 Dostalova
  et al. 2005 Dostalova et al. (unpublished
  results) Hoster D.W. Eating Disorders
  Obesity, anorexia nervosa, and bulimia nervosa.
  In Williams Textbook of Endocrinology. Ed.
  Wilson JD, Foster DW, W.B.Saunders Co., 1992.

79
The loss of fat mass is the main contributor to
weight loss of patients with AN
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
HOMA-IR 2.8 ? 0.38 0.8 0.31
Menstruation Yes - regular cycle Secondary amenorrhea
Means SEM
80
Complications of AN

• Hematological and electrolyte leukopenia with
  leukocytosis, alkalosis, hypokalemia,
  hypochloremia, elevated serum bicarbonate
  (vomiting), acidosis (laxatives), dehydration,
  lethargy, weakness
• Chemistry elevated liver enzymes, elevated serum
  cholesterol, carotinemia, elevation of amylase
  (vomiting)
• GI delay in gastric emptying sense (pp
  discomfort-early satiety-restricting behavior
  cycle), gastritis, esophageal erosions
  (vomiting) or rupture (binge eating)
• Long-term complications
• Osteoporosis
• Amenorrhea - persisting after weight recovery in
  50 of AN (warren and Vande Wielle 1973)
• Skeletal-muscular injuries (sprains, fractures)

81
Adipose tissue in anorexia nervosa

• Restrictive subtype of anorexia nervosa is
  accompanied by major disturbances of endocrine
  function of adipose tissue
• Most if not all of these disturbances are
  probably secondary to decreased food intake
  (rather than causative factors in this disease)
• The amount of fat in patients with anorexia
  nervosa is still high enough to prevent ectopic
  fat storage syndrome
• Most of the severe complications in AN patients
  results from extreme and long-term malnutrition

82
LEPTIN IN AN

• Falling leptin concentrations might mediate the
  neuroendocrine response to fasting (Ahima 1996,
  Chan 2003)
• Serum hypoleptinemia in AN consequence of fat
  loss, but contributor to metabolic and endocrine
  response (adaptive friendly vs. harmful
  complications)
• adaptive to save energy d. HPT, HPG vs.
  hematologic and infectious complications,
  amenorrhea, osteopenia

83
What is the role of leptin in malnutrition?

• Hypoleptinemia triggers complex adaptive
  response to limited energy sources (?body fat).
  This adaptation includes decreased energy
  expenditure, amenorrhea, immunodeficiency etc.

84
Serum leptin and soluble leptin receptor in
patients with eating disorders
85
Hypoleptinemia is the cause of the changes in the
number and function of T-lymphocytes in patients
with anorexia nervosa
86
(No Transcript)
87
Leptin in AN associates with ghrelin, BMI, fat
mass, glycerol and estradiol
ghrelin BMI BF glycerol estradiol
leptin r n p r n p -0.57 0.002 20 NS 0.64 0.002 20 0.52 0.01 29 0.82 0.04 20 0.49 0.02 29 -0.82 0.04 10 NS 0.49 0.04 16 NS
ghrelin r n p r n p - NS NS -0.52 0.04 20 -0.51 0.03 29 NS NS NS NS
Red anorexia nervosa, blue healthy women
88
serum hypoleptinemia in AN is not reflected in
the extracellular fluid of adipose
tissuehyperresistinemia in adipose tissue of AN
might contribute to inflammation
To make the situation complicated.
The biopsy of the scAT from woman with normal
weight (a) and from patient with AN (b)
89
Dissociation of local mRNA expression vs.
Circulating levels of adipokines in AN
Serum concentrations
Control AN
?
-
-
90
Short-term mild exercise reduces leptin in
patients with AN, but not in healthy women

• Control trial

Exercise
But the overnight fasting induced reduction of
leptin is lacking in AN
Dostalova et al. 2007
91
The postprandial leptin response is not present
in healthy women
Anorexia Nervosa
Healthy women
Dostalova et al. Unpublished data
92
GHRELIN IN ANOREXIA NERVOSA

• Fasting total and active ghrelin high in anorexia
  nervosa compensatory mechanism to increase
  caloric intake and induce state of positive
  energy balance
• Why they do not eat? Ghrelin hyposensitivity???
• But ghrelin unchanged in constitutively thin
  women without AN, higher in binge/purging type of
  AN

93
The postprandial ghrelin response is lacking in
patients with AN
Anorexia Nervosa
Healthy women
Nedvidkova et al. 2003
94
GHRELIN AND THE PATHOPHYSIOLOGY OF NUTRITIONAL
DISORDERS

• Ghrelin concentrations in obesity and AN opposite
  good marker of nutritional status
• The lack of ghrelin suppression after a meal in
  obese and AN critical factor in the
  pathophysiology
• Abnormalities in release of ghrelin/ insensivity
  to its effects involved in the altered food
  intake of obese and AN (Date et al. 2005)
• Ghrelin agonists/antagonists/analogues
  promising approach for future therapy

95
Pancreatic polypeptide in AN ?

• High fasting PP in anorexia nervosa are not
  corrected with short-term refeeding ?
  contribution to high weight relapse rate of AN
  (Konzig 2007)
• Postprandial PP response on high-fat meal
  increased in restrictive type of AN, but not in
  purging type ? appetite control effects of PP

96
Peptide YY and AN ?

• Poorly studied and with contradictory results
• in some studies high PYY levels in AN related to
  body mass index and body fat content
• But..
• Increased PYY activity in CNS may contribute to
  overfeeding in normal-weight bulimic patients
• Similarly PYY in AN may reflect the actual
  binge/purge behavior the explanation of
  inconsistent results in this field

97
Cholecystokinin in AN ?

• Low fasting CCK in AN normalized with weight
  restoration
• Diminished response of CCK on glucose load in AN
• High postprandial levels of CCK in AN may
  intesifying nausea and vomiting
• Earlier and greater rise of CCK in response to a
  liquid meal may contribute to the abnormal
  sensation of satiety in AN
• but these results were not found in all studies

98
Other alterations of neurohormonal regulation of
food intake in AN

• Central alterations of norepinephrine, dopamine
  and serotonine function in AN (and BN) (Torsello
  2007)
• Three known polymorphisms of AgRP in AN ?
  defective suppression of MC4-R downstream ?
  decreased feeding signal

99
Cancer anorexia

• Cancer anorexia-cachexia syndrome (Tisdale 1997)
• Observed in 80 of advaced-stage cancer
• One of the most frequent causes of death
  (Mantovani 2001)
• The role of proinflammatory cytokines (serotonin)
  released by cancer cells or immune systém in
  inducing satiety and anorexia, activation of
  anorexigenic pathway

100
Regulation of the feeding in cancer patients
Anorexia satiety
inhibition
101
Impaired response of adiponectin, ghrelin, and
leptin may play a role in the pathogenesis of
cancer cachexia syndrome
Breast and colon cancer patients
males
adiponectin
leptin
females
ghrelin
Wolf et al. 2006
102
FGF19 subfamily

• FGFs in general problems with pharmacological use
  due to mitogenic and proliferative activity
• vs. no recently described FGF19 and FGF21 (FGF23)
  specific cofactors essential for signalling
  determining specific effects in the tissue
  (?Klotho) and enabling unitary endocrinne effects
  (heparan sulfate)
• FGF21 hepatoadipokine, FGF19 GIT- liver axis
  acting in tissues where we expect disrupted
  metabolism in AN GIT (posprandial satiety)
  liver (insulin sensitivity) adipose tissue
  (endocrine production, lipolysis) dysbalanced
  regulation and cooperation of these tissues may
  contribute to metabolic complications in AN
  (weight relapses, hypoglycaemia, altered E
  metabolism) ev. FGF23 (osteoporosis)
• We are looking for candidates that could be the
  endcorine predictors of the efficiency of
  nutritional treatment in AN and/or for cadidates
  for pharmacological treatment of metabolic
  complications in chronic malnutrition

FGF23 Ca and P metabolism in bone
FGF19 Lipid and bile acid metabolism GIT liver
FGF21 Ketogenesis liver Lipolysis Adipose tissue
103
FGF19

• Produces predominantly in intestine
• Diurnal rhythm of secretion reflecting the evels
  of bile acids
• Enterohepatal regulation of bile acids synthesis
  postprandial increase of BA into intestine ?
  increased transcription of FGF19 (farnesoid X
  receptor for BA) ? FGF19 into the liver ?
  inhibition of BA synthesis (FGF19 decreases the
  synthesis of cholesterol-7-hydroxylase-limiting
  enzyme of BA synthesis) stimulation of lipid
  metabolism

104
FGF21 the missing link in the biology of fasting

• Predominantly expressed in the liver (humans
  100x higher expression than in AT) , BUT major
  endocrine effects in adipose tissue
• FREE OF proliferative and tumorigenic effects
  typical for other members of FGFs
• EFFECT DIFFERENT IN ANIMALS vs. HUMANS
• Mice circulating levels and hepatic expression
  ? by short-term fasting (12-24 h) and rapidly
  decreasing by food intake, FGF21 secreted from
  the liver consequently evokes adaptive metabolic
  response on fasting in adipose tissue (lipolysis)
  and in the liver (released FFA ketones)
• Humans decreases lipolysis in adipose tissue
  (increase of IS?), 2-day fasting no effect on
  serum FGF2, 74 increase of FGF21 after 7-day
  fasting, chronic malnutrition???
• Number of positive effects on IS a glucose
  homeostasis (new candidate molecule to treat
  T2DM)
• Stimulator of glucose uptake in mouse and human
  adipocytes independent on insulin (GLUT1)

105
FGF21 as a valuable predictor of the efficiency
of nutritional treatment in AN
106
Macrophage inhibitory cytokine-1

• crucial factor in cancer-related cachexia
  (anorexia, weight loss) in both animals and
  humans
• Patients with AN, obese and T2DM patients high
  circulating levels of MIC1 (regulation similar to
  cancer patients!)

CANCER
ANOREXIA NERVOSA
OBESITY AND T2DM