PATHOGENESIS OF OBESITY in Internal Medicine, REVIEWING ENERGY BALANCE (BASIC SCIENCE)

1. REVIEW ARTICLE
Pathogenesis and Pharmacologic Treatment of Obesity:
The Role of Energy Regulatory Mechanism
Mangatas SM Manalu*, IN Dwi Sutanegara**
ABSTRACT
Obesity has become a worldwide public health problem
affecting millions of people. This is a chronic, stigmatized,
and costly disease, rarely curable and is increasing in
prevalence to a point today where we define obesity as an
epidemic disease that not only in developed but also on
developing countries. The pathogenesis of obesity is largely
unknown, especially about energy regulatory mechanism that
involved wide area of neuroendocrinology that is very
interesting but very complex and makes internists “refuse”
to learn. Obesity occurs through a longstanding imbalance
between energy intake and energy expenditure, influenced
by a complex biologic system that regulates appetite and
adiposity. Obesity influences the pathogenesis of
hypertension, type 2 diabetes, dyslipidemia, kidney, heart,
and cerebrovascular disease. It is very wise for every
internist to learn the pathogenesis and treatment of this worldwide diseases. Until now, the available treatments, including
drugs, are palliative and are effective only while the
treatment is being actively used; and besides so many side
effects reported.
20%-30% of population.2 In Indonesian population in
Jakarta (1992-1993), obesity was found 10.9% (men) and
24% (women). In Bali, a survey conducted in JenahPeguyengan Kangin, Denpasar (urban area) in 1999
revealed prevalence of obesity 1.5%, while a study in Sangit,
Buleleng district, found total prevalence of 25.3%.4
The role of obesity, especially central obesity in type
2 diabetes mellitus (DM) and cardiovascular disease, has
long been recognized. Meanwhile, several studies on the
role of obesity in malignancy are still ongoing.
Recent studies showed that aside from fat tissue
function as excess energy storage, but also as endocrine
organ which produces various substances that affect body
metabolism.5
Etiology of obesity is often difficult to be determined.
It is important to understand the pathogenesis of obesity
specially energy regulation mechanism in order to
provide appropriate management of obesity.5,6
PATHOGENESIS OF OBESITY
Key words: obesity, pathogenesis, appetite, energy,
adiposity, pharmacologic treatment.
INTRODUCTION
Obesity is a condition of excess adipose tissue in the
body. The main diagnosis criteria for obesity among
Asians is body mass index (BMI) > 25 kg/m2.1 Primary
obesity is referred to as a condition where calorie intake
exceeds basal metabolic rate, while secondary obesity
occurs as a result of disorders such as hypogonadism
and hypothyroidism.2,3
The prevalence of obesity in UK in 1998 was 17%
(male) and 21%(female). In US (2001), obesity affected
* Department of Internal Medicine, ** Division of Endocrinology and
Metabolism, Department of Internal Medicine, Faculty of Medicine,
Udayana University / Sanglah Hospital Denpasar-Bali
42
The definite etiologic cause of obesity remains
unclear. There are 3 main factors involved in the
pathogenesis of obesity which are related to one another
in a complex interaction.
GENETIC FACTOR
It is estimated about 30% and 50% of body weight
gain is due to genetic factor. Study on families of obese
patients had proven the existence of significant
relationship of BMI between members of family among
one generation. Until recently, we have identified 7
genetic disorders which cause obesity in human. They
are gene signals of leptin, leptin receptor, melanocortin
receptor 4 (MC4), alpha-melanocyte stimulating hormone
(α-MSH), prohormone convertase 1 (PC-1),
proopiomelanocortin receptor (POMC), peroxisome
proliferators activated receptor gamma (PPAR-γ) gen.8-12
These genetic disorders consist of:
1. Monogenic disorder

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Pathogenesis and Pharmacologic Treatment of Obesity
In obesity due to single gene disorder, BMI may reach
as high as > 60 kg/m2, and has occurred since childhood. For example Prader-Willi syndrome which is
caused by disappearance of material expression of
paternal active genome in chromosome 15q11-13.
The manifestation of the syndrome is short gesture,
fat deposition in upper body, mental retardation, and
hypogonadism. This disorder is very rarely found.6
2. Multigenic disorder
Obesity phenotype is presumed as the result of
simultaneous interaction of genetic disorders and
environment factor. Various genes that have been
mentioned above are responsible for fat distribution,
energy expenditure during activity and rest, eating
habit, lipase protein activity, basal metabolic rate,
insulin induced-fat synthesis and decreased effect
of thermogenic factor of the food.
ENVIRONMENT FACTOR
Environment factors that contribute to obesity are
factors that cause increased food intake and decreased
physical activity.12 Those factors are listed in table 1.
12
Table 1. Environment Factors Contributing to Obesity
Environment factors suggested to promote overeating
Portion size
High fat/energy dense foods
High glycemic index of foods
Soft drinks
Sugar
Fast foods
Snack foods
Low calcium
Accessibility of food
Low cost of food
Taste of food
Variety of food
Environmental factors suggested to reduce physical
activity
Reduced need for physical labor in most jobs
No required physical activity in schools
Reductions in physical activity required for daily living, no sport
Competition from attractive sedentary activities:
- Television, video/DVD, computer games, internet
ENERGY BALANCE
Energy balance consists of intake regulation and
energy expenditure of the body. These two are
influenced by:
1. Psychological aspect
2. Organobiological aspect in form of energy
homeostasis that consists of:
a. Energy intake regulation
b. Energy expenditure regulation
In general, the pathogenesis of obesity can be
described in as figure 1.
Genetics
Environment
Obesity
Energy balance
Psycological factor
Organobiology/energy regulation
Figure 1. Pathogenesis of Obesity
PSYCHOLOGICAL ASPECT
Perception of hunger is many times determined by
mood, place, taste, type of food, eating behavior in
family, local culture and eating motivation. Energy
expenditure is much influenced by decreased motivation
to exercise due to facilities and technology and lack of
understanding on the benefit of physical activity for health
maintenance.13,14
ORGANOBIOLOGIC/HOMEOSTASIS ASPECT
Physiologically, energy intake is derived from food.
The energy is produced to maintained basal metabolic
rate (obligatory energy expenditure), adaptive
thermogenesis energy and energy for working.13
There is physiological balance between energy
intake and expenditure which is described in figure 2.
Energy allocation is further described in figure 3.
Energy Intake (food)
METABOLISM
Energy Storage (fat)
Total Energy Expenditure
= Heat produced + work on environment (when
organism is at rest, all energy expenditure
is equal to heat produced, i.e. thermogenesis)
Figure 2. Energy Balance
Total energy expenditure
Adaptive Thermogenesis
- Variable, regulated by the brain
- Responds to temperature and diet
- Occurs in brown adipocyte
mitochondria, skeletal
muscle, and
other sites
X
X
Physical activity - variable
Obligatory energy expenditure
Required for performance of cellular
and organ function
Figure 3. Energy Allocation
13
43

3. Mangatas SM Manulu, et al
If there were increased intake or decreased energy
expenditure, the body would try to reduce excess energy
and lower intake or increase energy expenditure. The
extra energy in the long term will be stored in form of fat
mass in adipose tissue. Protein and carbohydrate
storage is relatively stable, thus, condition that determines
the bodyweight in the long term is adipose tissue mass.1,13-15
A. Energy/food intake regulation
Physiologically, food intake is controlled by appetite
which is the result of stimulus interaction of food and its
inhibitors. Food stimulation is caused by increased need
and expenditure of energy in the form of hunger
sensation, while the inhibitory factor is in the form of
satiety. 5,13,14
Hunger is influenced by internal factors such as blood
glucose, insulin, ghrelin and external factors like
emotion, time, food availability and environment
factors. The sense of satiety has more roles in
determining food quantity and much more influenced by
internal factors.14,15 There is feedback mechanism of
food intake regulation that consists of:
• Center of intake regulation and energy expenditure
Hypothalamus is the center of information that
receives and processes regarding energy balance
status in the body through afferent signal derived from
gastrointestinal tract and adipose tissue. Ventromedial hypothalamic nuclei (VHN) stimulation causes
the release of neuropeptide of ‘satiety’ sensation. On
the other hand, stimulation of lateral, dorsomedial and
paraventriculi hypothalamic nuclei cause the
release of neuropetides of ‘hunger’. At the hidbrain,
there are solitary tract nuclei (STN) which receive
signal from gastrointestinal tract. Third brain ventriculi had arcuata nuclei which function as peripheral
signal transducer to special neuronal signal. Those
various nuclei are connected to one another and send
signals through neurons to cerebral cortex, hypofisis
brain stem cell and autonomic nerve system.
• Afferent Signal of Intake Regulation
There are 2 afferent signals which are classified as
hormonal and neuronal signal:
1. Hormonal signal
This afferent signal comes from adipose tissue,
gastrointestinal tract, thyroid glands, adrenal, muscles
and reproductive organs where signals from the two
first mentioned organs have more roles. These
signals deliver information on nutritional balance and
body fat mass. Functionally, hormonal signal consists
of short term signal coding of satiety, while the
longterm signal code energy balance in adipose
tissue (adipocyte signal).5,17-20
44
Acta Med Indones-Indones J Intern Med
a). Peripheral afferent signal of gastrointestinal tract
During eating and digestion process, cholecystokinin (CCK) is released due to mechanical
stimulation of gastric stretching. This hormone
delivers afferent signal through vagal nerve to
STN which then projects it to hypothalamus,
insular cortex and motoric nuclei of brain stem
cell resulting in sign of cessation of eating
processes.5,20 Many kinds of afferent signals from
gastrointestinal tract are shown in table 2.
b). Peripheral afferent signal of pancreas
Insulin, glucagons, and amylin are food intake
regulator. Physiological afferent signal of
pancreatic hormones are shown in table 3.
c). Adipocyte signal
In condition of excess energy exists, secretion
of insulin and leptin will increase as adipose
signal that gives information to hypothalamus. On
the contrary, in condition of insufficient energy,
there is increase of ghrelin.18,19 Adipose signal is
a long term signal although ghrelin and insulin
are rather short term signals.16-18 Main adipose
signals are:
Leptin
Leptin is coded by LEP gene at chromosomes 7q31.
This substance is assumed as one of cytokine family due
to its crystal structural form. Leptin is mainly produced
in the night by white adipose tissue although it is also
produced by the brown adipose tissue, gastric mucosa,
macrophage, mammary epithelium, myocites, and
placenta as well. Leptin level is in accordance with
visceral adipose tissue, circulates freely or protein binds
and is able to run across the blood brain barrier. In
condition of long fasting, leptin level will decrease and
the other way goes in excess food intake. Leptin
possesses receptors coded by gene 1p31. There are 5
types of leptin receptor (LEP-Ra, LEP-Rb, LEP-Rc,
LEP-Rd and LEP-Re) in hypothalamic tissue, brain, lung,
renal, muscle, liver, pancreatic β-cell, adrenal, hemopoetic
stem cell, ovary, and adipose tissue. Leptin secretion is
increased by high dose insulin, glucocorticoids, and
estrogen, while isopreterenol, adrenal β3 receptor
agonist, nicotine, high Zn diet, thiazolidinediones,
testosterone, and thyroxine will decrease it. Because
leptin secretion is in line with the amount of fat mass
tissue, thus obese patients have high level of leptin. This
fact has explained the role of leptin resistance in
pathogenesis of obesity. 24, 25 Physiology of leptin
consists of: a).Central physiology; by binding with
LEP-Rb in arcuate nuclei, leptin inform the condition of
excess energy to hypothalamus through sympathetic

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Pathogenesis and Pharmacologic Treatment of Obesity
20
Table 2. Afferent Signals from Gastrointestinal Tract
Site of
Peptide
Stimulus
Production
CCK
Protein and fat
Small intestine
Brain
GLP-1
Nutriens
Ileum/colon
Gut hormones
Gut neural signals
Ghrelin
Fasting
Stomach
Apo A-IV
Fat absorption
Intestine/liver
Enterostatin
Fat
Stomach/intestine
Bombesin
Gastric mucosa
Food ingestion
PYY 3-36
Oxyntomodulin
Carbohydrate, fat
Gut neurosignal
Carbohydrate
Gut neurosignal
Small intestine,
Colon
Small intestine
Site of Action
Effect on food intake
Vagal afferents
Decrease
Gastric emptying
Brain
Decrease
Brain/ARC
Brain/ARC
Vagal afferents
Vagal afferents
Brain/ARC
Brain/ARC
Increase
Decrease
Decrease
Decrease
Brain/ARC
Decrease
Decrease
5
Table 3. Regulatory Peptide of Food Intake/Apheren Signal of Pancreas
Peptide
Insulin
Amylin
Glucagon
Stimulus
Carbohydrate
Carbohydrate
Cephalic response
Site of
Production
b-cell
b-cell
a-cell
nerve system. This binding will then send signal through
JAK-2 (janus kinase-2) and signal transducer and
activator of transcription 3 (STAT-3) in thyrosine kinase
pathway that will suppress the expression of ‘hunger’
neuropeptide effector (orexigenic). Main orexigenic
substance are neuropeptide Y (NPY) and agouti related
protein (AGRP). Leptin increases sympathetic activity
which modulates thermogenesis through mitochondrial
uncoupling protein (UCP) induction of brown adipose
tissue.22-24 b). Peripheral physiology; Leptin modulates
peripheral signal of ‘satiety’ such as CCK signal. In
addition, it inhibits lipogenesis through inhibition of
acetyl-CoA carboxylase that makes malonyl-CoA as
mitochondrial b-oxidative inhibitor substance decrease.
Leptin increases mitochondrial oxidation and lipolysis and
make intracelullar fatty acid and triglyceride decrease.
Insulin resistance and lypogenesis in liver will decrease.
Leptin suppresses glucocorticoids and insulin production,
increases interleukin-2 secretion and T-naïve
proliferation. 22 Leptin and LEP-Rb binding increases
hormone sensitive lipase (HSL) activity which hydrolyzes
cholesterol esther of macrophages will then increase
protection against atherosclerosis.14
Ghrelin
Active form of ghrelin called n-octanoyl ghrelin is a
potential orxigenic substance. This hormone which is
found in gastric lamina propria capillary, intestine,
Site of Action
Brain
Brain
Liver/vagal afferents
Effect on
food intake
Decrease
Decrease
Decrease
kidney, placenta, hypofisis, and hypothalamus happen to
be endogenic ligand of growth hormone secretagoge
receptor (GHSR). It regulates appetite independently
from its effects on growth hormone secretion. Ghrelin
increases the expression of AGRP mRNA and NPY on
ARC neuron and inhibits vagal nerve activity.19,21,26 Strong
stimulation of ghrelin secretion is low blood glucose level
as signal to start eating. In weight loss condition,
synthesis of ghrelin is increased to stimulate appetite. In
obesity, plasma level of ghrelin is decreased and so that
obese patient will not gain extra energy. Ghrelin increases
adipose mass because it reduces fatty acid oxidation.
There has not been no report on the presence of ghrelin
resistance. By its effect on appetite and fat mass, ghrelin
has a role to regulate balance of energy both in short and
longterm of action. 20,21,27
Insulin
This hormone functions to facilitate glucose
influx into the cell and is necessary for fat synthesis and
storage. Insulin level and secretion correlated positively
with bodyweight and body fat content, especially white
fat. Obese patients have fat more than normal people so
that they will have basal and post prandial insulin higher
and finally cause insulin resistance. Hyperinsulinemia in
this condition increases fat absorption in adipose
tissue.14,18 Insulin receptor in ARC posseses anorexigenic
property and contains of a-subunit as insulin binding
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5. Mangatas SM Manulu, et al
Acta Med Indones-Indones J Intern Med
Increase appetite
Central
nervous
system
Ghrelin
Leptin
Insulin
Decrease
Cholecystokinin, fuel
molecules, vagal input,...
Stomach
Pancreas
Food
intake
Adipose Tissue
Energy stored
Peripheral adiposity signals
Gastro
intestinal tract
Energy ingested
Meal termination signal
Figure 4. Association Between Peripheral Signal Afferent and Adipose Signal in Intake Regulation
location and b-subunit with thyrosine kinase as
intracellular protein signal activator. Protein
produced by b-subunit that is called insulin
receptor substrate 1 (IRS-1) is coded by tubby gene (Tub).
Disturbance on Tub gene causes obesity. Insulin
injection to third brain ventriculi increases anorexigenic
effect of CCK and corticotropine releasing factor (CRF)
mRNA expression and decreases NPY expression. It is
clear that insulin has the catabolic effect on
central nervous system. When the level of insulin goes
high, insulin influx rate into the brain is not increased.
Insulin also has a role in long term signal processing
through its ability to determine how much fat is needed
and stored in the body. Insulin effect in peripheral and
central nervous system seems to counteracts to each
other. 14,16,18,20
Association Between Peripheral
Signal and Adiposity Signal
Afferent
Association between peripheral signal afferent and
adipose signal in intake regulation is shown in figure 4.
Interaction Between Adiposity Signals in
Hypothalamus
Hypothalamic ARC neurons are classified into 2
groups. First group expresses propiomelanocortin (PMC)
neuropeptide and Cocaine and amphetamine regulated
transcript (CART), while the second group expresses
NPY and AGRP. Leptin and ghrelin have receptors on
both group of neurons but with counteract expression.
Leptin stimulates POMC/CART and inhibits NPY/AGRP
while ghrelin acts the other way round. Leptin signal disturbance increases sensitivity to ghrelin but the other
counterparts issues had not yet been proven.14,20,27
46
NPYAGRP neurons send local collateral input through
gamma amino butyric acid (GABA) to POMC/CART
neurons. This will suppress POMC/CART and stimulate
the appetite. Ghrelin precipitates this local circuit while
ghrelin inhibits it.14,27 Association between adipose
signals in hypothalamus in intake regulation can be seen
in figure 5.
The similarity between leptin and insulin receptor
location is POMC neurons. Both work synergistically
resulting in hypophagia effect. An intracellular insulin
mediator called phosphatidyl 3-OH kinase is also known
to increase transduction of leptin anorexigenic signal. The
difference between these two signals is that
insulin signal describes more short term metabolic
changes while leptin has more roles in the long term
changes. Insulin secretion is in line with visceral white
fat mass, while leptin secretion represents total amount
of body fat. 13,18,19,23
2. Neuronal Signal System
The system is controlled by sympathetic and
serotonergic nervous system which possesses axis
that is very similar to adiposity signal axis. The role
of sympathetic nerve system in regulating of energy
intake is done by 2 actions. First by increasing
thermogenesis through norepinephrine release which
causes stimulation of mitochondrial UCP system. The
second one is through increasing epinephrine release
that will induce glucose and fatty acid oxidation.
Serotonin neurons in dorsal raphe nucleus midbrain
sends signals to PVN and VMH neurons through
POMC neuron system resulting in decreased food
intake. Damage of serotonin receptor 2C (5-HT2CR)

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Pathogenesis and Pharmacologic Treatment of Obesity
Leptin
Peripheral
Adiposity
Signals
Insulin
Ghrelin
(+)
(+) (-)
POMC
Neurons
(+)
(-)
Mc4r
(-)
Y2 (-)
NPY
Y1 (+)
AgRP
Comparison of POMC
& NPY Input
POMC
Dominant
Anorexia
Arcuate
Nucleus
NPY/AgRP
Neurons
GABA-NPY
a-MSH
(-)
Paraventricular and
other nuclei
NPY
Dominant
Hunger
Figure 5. Association Between Adipose Signals in Hypothalamus in Intake Regulation
causes hyperphagia and obesity. Sympathetic
neuronal signal system is also influenced by
corticosteroids, estrogen, testosterone, and
thyroxine.14,17
•
Effectors system of intake regulation
As the response to various afferents signals,
hypothalamus send efferent signals to arcuate nuclei
which then produce some effector neuropeptides of
feedback mechanism regulatory pathway of food intake.
Those neuropeptides are classified into 2 groups;
orexigenic and anorexigenic neuropeptides.15-16 Biological effectors of food intake are shown in table 4.
B. Energy expenditure regulation
Nutrients derived from food digestions will undergo
oxidative phosphorilation in mitochondria to form
adenosine-triphosphate (ATP) by releasing energy in form
of heat. The use of ATP and physical activity also
releases heat. This process is initiated by sympathetic
stimulation on b3-adrenergic receptor. The receptor
stimulation will activate protein kinase A effectors and
cyclic adenosine monophosphate (c-AMP) that has 2
effects. The first is an acute effect of increased lipolysis
and activation of UCP-1 on brown fat tissue and UCP-2
and UCP-3 of muscles. The second is a chronic effect
such as UCP gene transcription, mitochondrial biogenesis, hyperplasia, and brown adipose tissue recruitment
to white adipose tissue. POMC system regulates energy
expenditure through α-MSH neurons on melanocortine
receptor 4 (MC-4) by activating sympathetic nervous
system. Activation of POMC neurons is initiated by leptin
when energy storage in fat tissue is increased.13,15,16
Regulation of energy expenditure is shown in figure 6.
TREATMENT OF OBESITY
Treatment of obesity includes pharmacologic and
nonpharmacologic therapy. Non pharmacologic therapy
consists of dietary program, life style and eating habit
modification, exercise and surgical therapy. Weight loss
is gained gradually. Longterm goal of therapy is 10 % of
weight loss from the initial body weight, maintain BMI
< 23 kg/m2, lowering blood pressure and blood glucose,
risk factor management of obesity and glycemic
control.7,11, 28-30 Surgical therapy is indicated in:
1. Patient with obesity with BMI > 40 kg/m2 and or
body weight > 45 kg above mean normal weight of
population after age and sex adjustment
2. Patient with obesity with BMI 35-40 kg/m2 and has
comorbids like type 2 diabetes mellitus, hypertension,
heart failure, peripheral edema, sleep-apnea
syndrome, bronchial asthma, severe dyslipidemia,
esophagitis, cerebral pseudotumor, osteoarthritis,
thromboembolic
disorder
and
urinary
incontinents.7,11,29
PHARMACOLOGIC THERAPY OF OBESITY
In general, the classification of obesity drugs are as
follows:
1. Drugs that suppress the appetite (appetite
suppressants)
2. Drugs that inhibit nutrients absorption
3. Drugs that increase energy expenditure but have not
been approved for treatment of obesity such as
ephedrine. 27,29
Obesity drugs that will be discussed below are those
have been approved by the FDA, are shown in table 5.
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7. Mangatas SM Manulu, et al
Acta Med Indones-Indones J Intern Med
Table 4. Biological substances of food intake effectors.
Stimulatory (orexigenic)
Norepinephrine (NE, ? 2 receptor)
g Aminobutyric acid (GABA)
Neuropeptide Y (NPY)
Opioids
Galanin
Growth hormone-releasing
hormone (GHRH)
Melanotroph-concentrating
hormone (MCH)
Orexin A and B
Agouti-related protein (AGRP)
16
Inhibitory (anorexigenic)
Norepinephrine (NE, b receptor)
Serotonin (5-HT)
Dopamine
Histamine
Corticotropin-releasing factor (CRF)
a-melanocyte-stimulating hormone (a-MSH)
Cocaine-and amphetamine-regulated transcript (CART)
Neurotensin
Calcitonin-gene related peptide (CGRP)
Adrenomedullin
Oxytocin
Anorectin
Thyrotropin-releasing hormone (TRH)
Cyclo-histidyl proline jikatopiperazine (Cyclo-His-Pro)
Pituitary adenylate-cyclase activating polypeptide
Acidic fibroblast growth factor
Interleukin 1b (IL-1b).
Urocortin
Proopiomelanocortin (POMC ) / melanocortin (MC)
27
Table 5. Obesity Drugs Which are Approved by FDA
Generic name
Mechanism
DEA
schedule
Phendimetrazine
Noradrenergic
III
Benzphetamine
Diethylpropion
Phentermine
Sibutramine
Noradrenergic
Noradrenergic
Noradrenergic
Noradrenergic
and serotonergic
Gastrointestinal
lipase inhibitor
III
IV
IV
IV
Orlisat
Unscheduled
Appetite Suppressants
Norepinephrine can suppress appetite if binding to
adrenoreceptor α1, β2, and β3. This class of drug is
receptor agonist and norepinephrine reuptake inhibitor. For
examples, diethylpropion, benzphetamine and phentermine.
These drugs can increase neuronal norepinephrine release
and cause weight loss 3%-8% more than placebo. The side
effect is sympathetic tonus overdrive. Because of the
potent side effect, FDA did not recommend the use of
appetite suppressants for more than 12 weeks.27-29
Sibutramine
This drug inhibits norepinephrine presynaptic reuptake
and serotonin so that the effects of both neurotransmitters in central nervous system will increase. In a
multicenter study in Europe, sibutramine at doses of
10-20 mg/day along with low calories diet had lost weight
5-10% in 6 months. Body weight maintained successfully for 2 years in 80% subjects. It could decrease
triglyceride level as much as 4.5-42 mg/dl and increase
48
Side effects
Palpitations, tachycardia, insomnia,hypertensio
n, dry mouth, constipation
Same as phendimetrazine
Same as phendimetrazine
Same as phendimetrazine
Hypertension, tachycardia, headache,
insomnia, dry mouth, constipation
Loose stools, increased defecation,
oily discharge, fecal urgency, deficiency of
fat- soluble vitamins, flatulence
HDL cholesterol as much as 3-9 mg/dl. The side effect
of the drug is increased systolic pressure 0.3-2.7 mmHg
and diastolic pressure 1.6-3.4 mmHg and increased heart
rate 2-5 beats/minute. Intermittent therapy of sibutramine
for 12 weeks along with placebo for 7 weeks during
period of 48 weeks may reduce the side effect.27
Orlistat
This drug inhibits pancreatic lipase enzyme so that
hydrolysis of triglyceride to fatty acids lowers and
reduces fat absorption as low as 30%. There is no severe
systemic effect reported although fat soluble vitaminse
supplementation is needed. Side effects like diarrhea and
flatulence are relatively tolerated. Low calorie diet and orlistat
for 6 months resulted in weight loss of 5.9%-10%. Orlistat
reduces total cholesterol level, LDL and systolic and
diastolic pressure significantly. To reduce the side effect
of orlistat, it is recommended to use psylium mucilloid
concomitantly. There is no synergistic effect on
combination of orlistat and sibutramine.27,29-30

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Pathogenesis and Pharmacologic Treatment of Obesity
Hypothalamus
Paraventricular Nuclcus
Arcuate Neucleus
MC4R
Neurons Controlling
Autonomic Outflow
a MSH
neurons
Spinal cord
Sympathetic
MC4R Preganglionic
Neurons
Sympathetic nerves are activited
Diet is sense
by the brain
Norepinepltrine
b- AR
Brown adipocyte
cAMP
Protein Kinase A
Acute Effects
- stimulation of lipolysis
- Activation of UCP 1 activity
Chronic Effects
- UCP 1 gene transcirption
- Milochondrial biogenesis
- hyperplasia of brown adipocytes
white adipose tissue depots
13
Figure 6. Regulation Mechanism of Body Energy Expenditure
PHARMACOLOGIC THERAPY IN THE FUTURE
The drugs in the market recently have only shown
potency to reduce weight not more than 10%. Thus, it
encourages the search for new promising obesity drugs.
Leptin
This substance stimulates POMC neurons and
inhibits NPY neurons resulting in decreased sensation of
hunger. A study that used leptin recombinant until reach
dose of 0.3 mg/kg had failed to make significant weight
loss. This is assumed to be caused by leptin resistance.
Low dose leptin as matter of fact inhibits plasma thyroid
hormone and prevents energy expenditure reduction as
compensation of diet therapy. Thus, leptin is used more to
prevent weight gain after other anti obesity therapy than to
reduce weight itself. Strategy to cope with leptin resistance
is to activate leptin signal cascade from its receptor, cilliary
neutrophic factor, a cytokine STST-3 signal activator that
can reduce leptin resistance is also being studied.27,29
MC4 Agonis Receptor
A study found that this intranasal drug may reduce 1.68
kg fat mass, decrease leptin and insulin plasma each as
much as 24% and 20% subsequently after use for 6
weeks.27
Other Drugs
Ghrelin inhibitor, MCH receptor inhibitor, 11-b
hydroxysteroid dehydrogenase antagonist, enzyme that
converts cortisone to cortisol in adipose tissue and liver
and reduces effect of leptin in hypothalamus is still in
ongoing study.27,29
CONCLUSION
Three main factors regarding pathogenesis of
obesity are genetics, environment and energy balance.
Obesity may be caused by increased intake or decreased
body expenditure. Energy intake is mainly regulated by
appetite especially the sense of satiety. Feedback
mechanism of appetite regulation consists of center
regulation in hypothalamus, various afferent signals and
neuropeptide effectors. Short afferent signal comes from
the gastrointestinal tract while the longterm signal comes
from the adipose tissue. Interaction between leptin with
insulin and ghrelin on POMC and NPY neurons in
hypothalamus regulates the intake. Obesity may be
caused by leptin resistance, hyperinsulinemia, ghrelin
hypersecretion or disturbed interaction between the three
substances. Other energy regulation systems are
serotonine and cathecolamine systems. Energy
expenditure is mainly regulated by sympathetic systems
through adrenergic receptor β3 by mitochondrial
activation. Pharmacologic therapy of obesity commonly
known recently still cannot decrease bodyweight
significantly and this has encouraged the searching of
newly promising obesity drugs.
49

9. Mangatas SM Manulu, et al
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