Obesity

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Port Said University
Faculty of Science
Chemistry& Biochemistry Department
Hormones in relation to
obesity
(Obesity and Hormones)
Presented by/
Mai Hisham Ahmed BerBer
supervised by/
Dr. Lamiaa Abdou Lateaf Ali Barakat
2013

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Faculty of Science
Chemistry& Biochemistry Department
Hormones in relation to
obesity
(Obesity and Hormones)
Presented by/
Mai Hisham Ahmed BerBer
supervised by/
Dr. Lamiaa Abdou Lateaf Ali Barakat
Presented to
Faculty of Science
Biochemistry Department
4th
level
2013

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Table of content
1 . Overview.
2. Introduction
3. CAUSES OF OBESITY
3.1. Energy Balance in the Development of Obesity
3.2. Dietary Intake
3.2.1. Macronutrient composition of the diet
3.2.2. High fat diets
3.2.3.Energy dense foods and drinks
3.2.4. Fibre content in the diet
3.2.5. Food palatability
3.3. Energy Expenditure
3.4. Physical Activity
3.4.1. Exercise and appetite
3.4.2. Health benefits of physical activity
3.5. Psychosocial Factors contributing to Obesity
3.5.1. Introduction
3.5.2. Hunger and appetite
4. Body mass index
4.1 .Calculation of BMI
4.2. Classification of BMI
5. Hypothalamus
5.1. Hypothalamic nuclei involved in appetite control
5.1.1. Arcuate nucleus (ARC)
5.1.2. Para ventricular nucleus (PVN)
5.1.3. Lateral hypothalamic area (LHA)
5.1.4. Dorsomedial nucleus (DMN)
5.1.5. Ventromedial nucleus (VMN)
5.2. Adiposity signals acting on the hypothalamus
5.3. Interactions between the brainstem and Hypothalamus
6. Gut hormones
6.1. Orexigenic peripheral neuropeptides
5.1.2. Ghrelin
6.2. Anorectic peripheral peptides
5.2.1. Cholecystokinin (CCK)
6.5.2.2. Leptin
6.2.3. Peptide YY (PYY)
6.5. Oxyntomodulin
6.6.Pancreatic polypeptide (PP)
7. The Central Effects of Thyroid Hormones on Appetite

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7.1. Introduction
7.1.1. Effects of Thyroid Hormones on Food Intake
7.1.2. Effects of Nutritional State on Thyroid Hormones
7.1.3. Thyroid Dysfunction and Body Weight State on Thyroid
Hormones
7.3. Thyroid Dysfunction and Body Weight
8. Growth Hormone (GH) secretion
8.1. Metabolic and nutritional factors
8.1.1Glucose
8.1.2. Insulin
8.1.3. Aminoacids
9. Sex hormones
10. Treatment alternatives for obesity
11. Surgery for the treatment of obesity
12 .References

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List of figure
Fig1………….The fundamental principles of energy balance and
regulation.
Fig2………………………………………… anatomy of Hypothalamus.
Fig3……… Pathways are shown between the brainstem, hypothalamus,
cortical areas and reward circuitry known to regulate appetite control.
Fig4...............................................................The main hypothalamic
nuclei, neuropeptides and pathways involved in the regulation of
appetite.
Fig5...........................................................Chemical structure of Ghrelin.
Fig6…………………. Chemical structure of Cholecystokinin (CCK).
Fig7…………………………………….. Chemical structure of Leptin.
Fig8………………………………..Chemical structure of Peptide YY.
Fig9………………………………….. Chemical structure of Amylin.
Fig10…………………………………… Chemical structure of Insulin.
Fig11…………………………………. Chemical structure of Bombesin.
Fig12…………………… Chemical structure of Glucagon like peptide-1.
Fig13……………………………………Chemical structure of Serotonin.
Fig14…………………………… Chemical structure of Neuropeptide Y.
Fig15…………………………………… Chemical structure of Orexins.
Fig16…………………………………… Chemical structure of Galanin.
Fig17……………………. Chemical structure of Pancreatic polypeptide.
Fig18………………... Schematic diagram of central appetite regulation.
Fig19………. Effect of fasting on the hypothalamo-pituitary-thyroid axis.
Fig20………... Central neuroendocrinological control of appetite and food intake.

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1.Overview:
Obesity is a serious medical condition whose prevalence is increasing in
developing countries also. This growing incidence represents a pandemic
that needs urgent attention if the potential morbidity, mortality, and
economic tolls that will be left in its wake are to be avoided. Obesity
predisposes to increased risk of a number of medical conditions including
type II diabetes mellitus, hypertension, coronary heart disease,
osteoarthritis, respiratory problems and cancers of breast, endometrium,
prostate, bowel cancers (1,2). Obesity represents a state of excess storage
of body fat. Although very similar, the term overweight is defined as an
excess body weight for height.
The body mass index (BMI), also known as the Quetelet index is a WHO
accepted index for classifying the degree of obesity. Standards defining
overweight and obesity on the basis of BMI were developed by the
International Obesity Task Force of the World Health Organization. BMI
= (weight [kg])/ (height[m] 2). Under this convention for adults, grade 1
overweight (commonly and simply called overweight) is a BMI of 25–
29.9 kg/m2. Grade 2 overweight (commonly called obesity) is a BMI of
30–39.9 kg/m2. Grade 3 overweight (commonly called severe or morbid
obesity) is a BMI greater than or equal to 40 kg/m2.
The laws of thermodynamics are applicable here also because if energy
expenditure by the body is less than the consumption, it will be stored in
the body in the form of adipose tissue. Appetite regulation is important
because it modulates the energy consumption side of the equation.
Appetite includes various aspects of eating patterns such as frequency
and size of eating episodes (gorging versus nibbling), choices of high fat

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or low fat foods, energy density of foods consumed, variety of foods
accepted, palatability of diet and variability in day-today intake. Feeding
behavior is controlled by a series of short-term hormonal, psychological
and neural signals that derive from the gastrointestinal tract, such as
cholecystokinin whereas other signals may initiate meals, such as the
recently discovered hormone, ghrelin. Other hormones such as insulin
and leptin, together with circulating nutrients, indicate long-term energy
stores. All these signals act at several central nervous system (CNS) sites
but the pathways converge on the hypothalamus, which contains a large
number of peptides and other neurotransmitters that influence food
intake. As energy deficit is most likely to compromise survival, it is not
surprising that the most powerful of these pathways are those that
increase food intake and decrease energy expenditure when stores are
depleted. When energy stores are low, production of leptin from adipose
tissue, and thus circulating leptin concentrations fall, leading to
increased production of hypothalamic neurotransmitters that strongly
increase food intake, such as neuropeptide Y (NPY), galanin and agouti-
related protein (AGRP) and decreased levels of a-melanocyte-stimulating
hormone (a-MSH), cocaine and amphetamine-regulated transcript
(CART). The hypothalamus has been recognized as a central region of
feeding regulation (3,2) . The appetite control system of the brain
normally establishes a weight ‘set-point’ and tries to maintain it even
when food supplies vary a great deal.

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2.Introduction:
Obesity is one of the major health challenges throughout the world, due
to its association with an array of vascular, metabolic, and psychosocial
complications (4, 5). Obesity is traditionally associated with populations
in Europe and North America; however Asian countries such as Japan
have recently may reflect changes in dietary patterns and lifestyles (6, 7)
reported increasing pre valences of obesity, which Obesity is a state in
which energy intake chronically exceeds energy expenditure. Body weight
is tightly regulated by complex homeostatic mechanisms involving the
hypothalamus and brainstem which integrate inputs from higher cortical
centres with peripherally derived signals of the body’s nutritional and
energy status. In the hypothalamic arcuate nucleus (ARC), there are two
neuronal populations with opposing effects on food intake: neurons
which co express neuropeptideY (NPY) and agouti-related peptide
(AgRP) which stimulate food intake, whereas neurons coexpressing
proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated
transcript (CART) suppress food intake (Figure 1). Within the brainstem,
the dorsal vagal complex (DVC) consisting of the dorsal motor nucleus of
vagus (DVN), area postrema (AP), and the nucleus of the tractus
solitarius (NTS) plays a pivotal role in relaying of peripheral signals
such as vagal afferents from the gut to the hypothalamus (8). In human,
higher cortical centres are implicated in psychological and emotional
factors which can drive food intake beyond homeostatic requirements. In
addition, the corticolimbic pathways are responsible for reward-
associated feeding behaviour. This article summarises our current
understanding of the role of gut hormones in appetite regulation and its
potential as therapeutic targets for obesity.

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3.CAUSES OF OBESITY:
3.1. Energy Balance in the Development of Obesity:
Obesity can result from a minor energy imbalance, which lead to a
gradual but persistent weight gain over a considerable period. Some
researchers have hypothesized that energy imbalance is the result of
inherited metabolic characteristics; whereas others believe it is caused
by poor eating and lifestyle habits, that is “gluttony and sloth”.
Positive energy balance occurs when energy intake is greater than energy
expenditure and promotes weight gain (Figure 1). Conversely, negative
energy balance promotes decrease in body fat stores and weight loss.
Body weight is regulated by a series of physiological Processes, which
have the capacity to maintain weight within a relatively narrow range
stable weight). It is thought that the body exerts a stronger defense
against under nutrition and weight loss than it does against over-
consumption and weight gain.
Figure 4 also suggests that positive energy balance and weight gains are
influenced by powerful societal and environmental forces which may
overwhelm the physiological regulatory mechanisms that operate to keep
weight stable. These include increasing automation, lack of recreational
facilities and opportunities, increase in food variety and availability.
Moreover, the susceptibility of individuals to these influences is affected

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by genetic and other biological factors such as sex, age and hormonal
activities, over which they have little or no control(9).
Dietary intake and physical activity are important contributing factors in
the development of obesity. If calorie intake is in excess of requirement it
will be stored mainly as body fat (Figure 1). If the stored body fat is not
utilized over time, it will lead to overweight or obesity.
Inter-individual variations in energy intake, basal metabolic rate,
spontaneous physical activity, the relative rates of carbohydrate-to-fat
oxidation, and the degree of insulin sensitivity seem to be closely involved
in energy balance and in determining body weight in some individuals
(10).
(Figure 1)
(Figure 1): The fundamental principles of energy balance and
regulation

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* TEF = thermic effect of food; BMR = basal metabolic rate; CHO =
carbohydrate.
Source: WHO (1998)
3.2. Dietary Intake:
3.2.1. Macronutrient composition of the diet:
The association between energy intake and body weight relies on the ease
with which excess macronutrients can be deposited as adipose tissue. The
energy cost of nutrient storage is not identical for all macronutrients. The
cost of fat storage from dietary fat is the lowest, followed by
carbohydrate and protein (11). Macronutrients with a low storage
capacity such as protein and carbohydrate will be preferentially oxidized
when intakes exceeded requirements. Hence, excess dietary fat is more
likely to be stored in the body and this capacity is unlimited (12,13). The
caloric content of fat is also more than twice that of protein or
carbohydrate (Table 1).

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In summary, after a meal the body has a specific order in which it burns
up the fuels, that is, alcohol, followed by protein then carbohydrate and
finally fat.
(Table 2) highlights the main characteristics of the macronutrients of
which fat seems to be the key macronutrient which undermines the body’s
weight regulatory systems since it is very poorly regulated at the level of
both consumption and oxidation.
Although high protein intakes may appear to be advantageous in
controlling energy intake and contributing to good body weight
regulation, high protein intakes (especially animal protein) have been
associated with some adverse health consequences such as renal disease,
cancer and cardiovascular diseases(9).

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3.2.2. High fat diets:
Foods or meals that are high in fat are smaller in weight or volume than
high carbohydrate foods or meals of similar energy content (14). Dietary
fat content is directly correlated with energy intake, produces only weak
satiation in comparison with protein and carbohydrate, and is thought to
be processed efficiently by the body. A number of studies found that
individuals on a high-fat diet are more prone to become overweight (15).
3.2.3.Energy dense foods and drinks:
Consuming too much or too often high calorie foods and drinks may
increase the total calories and thus result in obesity (15). The energy
density of foods may be contributed by its macronutrient contents. A high
fat food will often be labelled as energy-dense. Low fat food products
may also be high in calories and therefore should not be eaten in excess.
Beverages containing substantial amounts of sugar or alcohol can also
contribute to excessive calorie intake.
3.2.4. Fibre content in the diet:
A diet with adequate amounts of fibre-containing foods is usually less
energy dense. Its greater bulk has a short-term satiety effect, can help to
prevent overeating and reduce risk of obesity(16). This can be achieved
by including fruits, vegetables, whole grain cereals, pulses and legumes
in the diet. Efforts to increase dietary fibre intake should be gradual to

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minimize discomfort such as bloating and flatulence. It is important to
drink a lot of water when increasing fibre intake.
3.2.5 .Food palatability:
Palatability is defined as the momentary subjective orosensory
pleasantness of a food, which indicates the sensory stimulation to eat. It
is one of the most powerful influences in promoting calorie over-
consumption (positive energy balance) by increasing both the rate of
eating and the sense of hunger during and between meals. Perceived
palatability of foods plays a major role in determining which foods are
selected over others (17). It has also been argued that palatability is
associated with the energy density of foods. Foods that are energy dense
are more palatable than those of lower energy density (18). Fat is
associated with palatability and pleasurable mouth-feel that can induce
behaviour which favours over-consumption leading to obesity (19).
3.3. Energy Expenditure:
Total energy expenditure has three main components, namely, basal
metabolic rate (BMR), thermogenesis or thermic effect of food (TEF)
and physical activity (Figure 1).
Basal metabolic rate is the energy expended by a person who is fasting
and at rest in the morning under comfortable ambient conditions. The key
variable of energy output in an individual is the degree of physical
activity. In a dynamic phase, in which an individual gains weight as a
result of energy intake exceeding energy expenditure over a prolonged

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period, BMR will increase due to the larger fat-free mass (including that
of the expanded adipose tissue) as well as to an additional energy cost of
activity imposed by the extra weight(20).
Thermogenesis is the increase in basal metabolic rate in response to
stimuli such as food intake, cold or heat exposure, psychological
influences such as fear or stress, or the administration of drugs or
hormones. The thermic effect of food (the major form of thermogenesis)
accounts for approximately 10% of the total daily energy expenditure.
Physical activity is defined as any bodily movement produced by skeletal
muscles that result in a substantial increase over the resting energy
expenditure (21) .It is the most variable component of daily energy
expenditure, which may account for a significant number of calories in
very active individuals. Sedentary adults however, exhibit a range of
physical activity that still represents about 20% to 30% of the total
calorie expenditure.
3.4. Physical Activity:
3.4.1. Exercise and appetite:
Obese women did not compensate the higher energy expenditure induced
by exercise with increased intake, and thereby obtained a significant
negative energy balance on exercise (22). This suggests that those who
have an excess amount of energy stored may particularly benefit from
regular exercise. Hunger can be temporarily suppressed by intense
exercise, and possibly by low-intensity exercise of long duration. Hence,
there is no supporting evidence for the common perception that exercise

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stimulates appetite, leading to an increased food intake that even exceeds
the energy cost of the preceding activities.
3.4.2. Health benefits of physical activity:
Physical activity has been shown to improve the physiological aspects of
our body system such as cardiovascular, respiratory, metabolic and
weight control. There is convincing evidence that physical activity
reduces risks of obesity, type 2 diabetes, certain cancers and
osteoporosis.
Other benefits of physical activity includes becoming more energetic,
improved self esteem, increased resistance to stress, build stronger
muscles and joints, increased fitness and flexibility, and living a healthier
and longer independent life. On the other hand, physical inactivity and
sedentary lifestyle increase risk of obesity (16).
3.5.Psychosocial Factors contributing to Obesity:
3.5.1. Introduction:
Psychosocial factors take precedence in terms of contribution to obesity
because genetic changes do not occur quick enough to warrant the
increase of obesity cases around the world (23). Calorie intake and use
largely depend on behaviour, which are food-related and non-food
related. The significance of behavioural factors in weight gain is that it
can be modified more easily than genetics.

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3.5.2.Hunger and appetite:
Hunger is a physiological response to a need for food triggered by stimuli
acting on the brain (24). It can be affected by a number of factors such as
the size and composition of preceding meal, habitual eating pattern,
exercise, physical and mental states(25) .In a normal eating pattern
hunger begins after four to six hours after eating, when food has left the
stomach and much of it has been absorbed by the body. This pattern is
highly influenced by psycho physiological factors such as smell, as well
as environmental interactions (26).
Individuals who restrict food consumption at each meal may feel extra
hungry for a few days, but then hunger diminishes for a time. However, at
some point of food deprivation, hunger can be uncontrollable and lead to
bouts of overeating that more than make up for the calories lost. The
stomach capacity can also adapt to larger food quantities and until a
normal meal size no longer feel satisfying.
At some point during a meal, the brain receives stimuli from several
sources that enough food has been eaten. This process is called satiation
(25). A lack of satiety between meals can lead to overeating when a
mealtime arrives. In some cases this sets up a cycle of starvation and
binging, which lead to overeating. The choice of food may affect satiety –
some foods seem to sustain satiety for longer period than others. In
general foods high in protein and fibre sustain satiety longer than those
high in fat or sugar.

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4.Body mass index:
Body Mass Index (BMI) provides the most useful albeit crude population
level measure of obesity and can be used to estimate the relative risk of
disease in most people (27).
4.1 Calculation of BMI:
BMI is defined as weight in kilograms divided by the square of the height
in meters (kg/m2).
body weight (kg)
BMI =_________________
height (m)2
where kg = kilogram, m = meter.
4.2 Classification of BMI: (Table3)

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5. Hypothalamus:
The hypothalamus is a portion of the brain that contains a number of
small nuclei with a variety of functions. One of the most important
functions of the hypothalamus is to link the nervous system to the
endocrine system via the pituitary gland (hypophysis).
The hypothalamus is located below the thalamus, just above the brain
stem. In the terminology of neuroanatomy, it forms the ventral part of the
diencephalon . All vertebrate brains contain a hypothalamus. In humans,
it is roughly the size of an almond.
The hypothalamus is responsible for certain metabolic processes and
other activities of the autonomic nervous system. It synthesizes and
secretes certain neurohormones, often called hypothalamic-releasing
hormones, and these in turn stimulate or inhibit the secretion of
pituitaryhormones. The hypothalamus controls body temperature,
hunger, thirst,fatigue, sleep, and circadian cycles. (Figure2)
http://www.studyblue.com/notes/note/n/limbic-system/deck/1241563

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5.1.Hypothalamic nuclei involved in appetite control:
The main regions of hypothalamus involved in feeding and satiety are:
5.1.1.Arcuate nucleus (ARC):
The ARC is a key hypothalamic nucleus in the regulation of appetite. In
mice, lesions of the ARC result in obesity and hyperphagia (28). Its
proximity to the median eminence and the fact that the ARC is not fully
insulated from the circulation by the blood brain barrier means it is
strategically positioned to integrate a number of peripheral signals
controlling food intake. There are two major neuronal populations in the
ARC implicated in the regulation of feeding. One population increases
food intake and co-expresses neuropeptide Y (NPY) and agouti-related
protein (AgRP). The second population of neurons co-expresses cocaine-
and amphetamine-related transcript (CART) and pro-opiomelanocortin
(POMC) and inhibits food intake. Neuronal projections from these two
populations then communicate with other hypothalamic areas involved in
appetite regulation such as the PVN, DMN and LHA (29).
5.1.2.Para ventricular nucleus (PVN):
Para ventricular nucleus (PVN) is the main site of orticotrophin
releasing hormone (CRH) and thyrotropin releasing hormone (TRH)
secretion. Numerous neuronal pathways implicated in energy balance
converge in PVN, including major projections from NPY neurons of the
ARC, Orexins, POMC derivative a-melanocyte stimulating hormone (a-
MSH) and the appetite stimulating peptide galanin. Thus PVN plays a

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role in the integration of nutritional signals with the thyroid and
hypothalamic- pituitary axis (1).
Microinjection of almost all known orexigenic peptides into the PVN,
including NPY and AgRP stimulate feeding (30, 31). NPY/AgRP neurons
from the ARC communicate with PVN neurons containing thyrotrophin
releasing hormone (TRH) (32) which has been implicated in the control
of energy balance, by contributions to both food intake and energy
expenditure (33).
5.1.3.Lateral hypothalamic area (LHA):
Lateral hypothalamic area (LHA)is the classical ‘feeding centre’, also
contains glucose-sensitive neurons that are stimulated by hypoglycemia
(by ascending pathways from brainstem) and it is crucial in mediating the
marked hyperphagia which is normally induced by hypoglycemia(34).
The LHA receives neuronal projections from the ARC and contains the
orexigenic neuropeptides melanin concentrating hormone (MCH) and
orexins. NPY, AgRP and α-MSH immune reactive terminals are extensive
in the LHA and are in contact with MCH and orexin expressing cells
(35). MCH immune reactive fibers also project to the cortex, brainstem
and spinal cord (36). In humans, two MCH receptors have been cloned in
humans, Mchr1 and Mchr2 whereas in rodents only Mchr1 has been
identified. Mchr1 knockout mice have increased energy expenditure, loco
motor activity and are resistant to diet-induced obesity (37). In contrast,
injection of Mch into the lateral ventricle of rats increases food intake
and fasting increases the expression of Mch mRNA (39). Orexin A and B
act via two receptors, OX1R and OX2R and ICV administration of these

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peptides increases food intake (39). However, subsequent studies have
proposed that this may reflect associated heightened arousal and reduced
sleep (40).
5.1.4.Dorsomedial nucleus (DMN):
Destruction of the DMN results in hyperphagia and obesity (41). The
DMN contains a high level of NPY terminals (42) and α-MSH terminals
originating in the ARC (43). Α-MSH fibers also project from the DMN to
the PVN terminating on TRH-containing neurons (44). In diet-induced
obesity, obese agouti mice and Mc4r knockout mice, NPY mRNA
expression is increased in the DMN (45, 46).
5.1.5.Ventromedial nucleus (VMN):
Ventromedial nucleus (VMN) is mainly acting as satiety centre. It has
been identified as a key target for leptin, which acts on the hypothalamus
to inhibit feeding, stimulate energy expenditure and cause weight loss.
Lesions of either ventromedial hypothalamic nuclei or PVN produce
syndromes of hyperphagia and obesity (47).
Neuroimaging studies in humans have shown increased signal in the area
of the VMN following an oral glucose load (48). The VMN contains a
large population of glucoresponsive neurons and receives NPY, AgRP
and POMC neuronal projections from the ARC. Brain-derived
neurotrophic factor (BDNF) is highly expressed in the VMN and lateral
ventricle administration of BDNF reduces food intake and body weight

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(49). It is thought that ARC POMC neurons have a role in activating
VMN BDNF neurons to decrease food intake (50).
5.2.Adiposity signals acting on the hypothalamus:
Adipokines are secreted by adipose tissue and include leptin, adiponectin
and resistin. They have been shown to act via the hypothalamus to affect
food intake and energy expenditure (51). Leptin is secreted by adipocytes
and circulates at concentrations proportional to fat mass. Rodents
lacking leptin (ob/ob mice) or the leptin receptor (db/db mice and Zucker
fa/fa rats) are obese and hyperphagic. In humans, the rare condition of
leptin deficiency causes severe obesity which can be ameliorated by
peripheral leptin administration (52).
Circulating leptin crosses the blood brain barrier and binds to the long
form of the leptin receptor, Ob- Rb, in the hypothalamus (53). The Obr
receptor is expressed widely within the hypothalamus but particularly in
the ARC, VMN, DMN and LHA. Using viral mediated gene expression,
chronic leptin over-expression in the ARC, PVN and VMN results in
reduced food intake (54). In the ARC, Ob-Rb mRNA is expressed by both
NPY/AgRP and CART/POMC neurons. Leptin directly activates anorectic
POMC neurons and inhibits orexigenic AgRP/NPY neurons resulting in
an overall reduction in food intake (55).
Circulating insulin rises in response to a glucose load and like leptin,
circulating levels reflect fat mass. Insulin crosses the blood brain barrier
via receptor-mediated transport. Insulin receptors are widely distributed
in the brain particularly in hypothalamic nuclei involved in the regulation
of food intake. Insulin has an anorectic effect when administered ICV or

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directly into the VMN, an effect which is reversed by insulin antibodies
(56). The precise mechanism by which insulin inhibits food intake is still
unclear although administration of insulin into the 3rd ventricle of fasted
rats increases ARC POMC mRNA expression and reduces food intake
(57). This anorexigenic effect of insulin is blocked by melanocortin
antagonists (57).
5.3Interactions between the brainstem and Hypothalamus:
The hypothalamus is often regarded as the “gate keeper” of appetite
signalling as it also receives input from the cortex, brain stem and the
periphery (Figures 3,4)milarly to the ARC, the area postrema of the brain
stem also possesses an incomplete blood brain barrier. As such,
peripheral satiety signals can also act directly on brainstem structures.
Extensive reciprocal neuronal pathways exist between brainstem and
hypothalamic appetite circuits to provide an alternative pathway through
which circulating satiety factors can communicate with the hypothalamus
(58,59). An additional major link between the gastrointestinal tract and
the brain exists via the vagus nerve. Cell bodies of afferent fibers of the
abdominal vagus nerve are located in the nodose ganglia, which project
onto the brainstem. Here, the dorsal vagal complex (DVC) (consisting of
the dorsal motor nucleus, the area postrema, and the sensory nucleus of
the tractus solitarius (NTS)) contains projections to hypothalamic and
higher centers (58,59).

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(Figure 3)
NTS = nucleus tractus solitarius; amyg = amygdala; n. accumbens =
nucleus accumbens.
(Figure 3): Pathways are shown between the brainstem, hypothalamus,
cortical areas and reward circuitry known to regulate appetite control.
There are also projections from hypothalamic nuclei to the pre-frontal
cortex, involved in conditioned taste aversion, as well as reward centres
such as the amygdala and nucleus accumbens. Gut hormones acting via
vagal afferents act on nuclei within the brainstem which in turn signal to
the hypothalamus. Some gut hormones may also act directly on
hypothalamic nuclei via the circulation and across an incomplete blood
brain barrier. Leptin is also thought to act directly on the brainstem
nuclei as well as hypothalamic nuclei suggesting that it can modulate
appetite through different pathways.

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(Figure 4)
ARC = arcuate nucleus; PVN = paraventricular nucleus; VMN =
ventromedial nucleus; DMN = dorsomedial nucleus; LHA = lateral
hypothalamic area; BDNF = brain-derived neurotrophic factor; CB1=
endocannabinoid receptor 1; MCH = melanin concentrating hormone;
CCK = cholecystokinin; GLP-1 = glucagon-like peptide 1; OXM =
oxyntomodulin; PYY = peptide YY; AgRP = agouti related protein; NPY
= neuropeptide Y; POMC = pro-opiomelanocortin; CART = cocaine-
and amphetamine-related transcript; AMPK = adenosine mono-
phosphate protein kinase.
(Figure 4): The main hypothalamic nuclei, neuropeptides and pathways
involved in the regulation of appetite. Circulating hormones act directly
on the ARC affecting downstream pathways which modulate appetite
control. In the ARC, orexigenic neurons co-express NPY and AgRP,
whereas neurons co-expressing POMC and CART are anorexigenic.

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6.Gut hormones :
The GI-pancreatic complex is the largest endocrine organ in the body
and a source of important regulatory peptides. Cholecystokinin was the
first to be implicated in the short-term control of food intake (60), and
other appetite-regulating hormones have subsequently been
characterized. Of these, ghrelin is the only known orexigenic gut
hormone, whereas a number of satiety factors exist, including glucagon-
like peptide (GLP)-1, oxyntomodulin (OXM), peptide YY (PYY), and
pancreatic polypeptide (PP) (61). Unlike leptin, which is thought to
signal longer-term energy status, these gut hormones appear to act as
meal initiators and terminators. Alterations in levels of gut hormones
after bariatric surgery may contribute to the appetite suppression and
sustained weight loss seen in patients undergoing this procedure and
supports the development of these hormones as therapeutic targets
(62,63).
6.1. Orexigenic peripheral neuropeptides:
6.1.2.Ghrelin:
This 28–amino acid peptide is synthesized principally in the stomach
(64). It acts via the growth hormone secretagogue receptor to increase
food intake in rodents (65) and also acts to stimulate food intake in
humans (66,67). Clinical studies have thus far concentrated on its use as
an orexigenic agent in conditions characterized by anorexia and
cachexia (68–71). Antagonists to ghrelin have been used in preclinical

29
studies, however, paving the way for possible future evaluation as a
therapy for obesity in humans (72).
Ghrelin is produced by the stomach and acts as an endogenous ligand on
the growth hormone secretagogue(GHS) receptor. Although the majority
of ghrelin is produced peripherally, there are ghrelin immunoreactive
neurons within the hypothalamus that have terminals on hypothalamic
NPY/AgRP, POMC and CRH neurons (73), as well as orexin fibres in the
LHA (74). Ghrelin initiates hunger prior to a meal and stimulates food
intake when injected directly into the PVN (75). Peripheral and central
administration of ghrelin increases c-fos expression in ARC NPY/AgRP
neurons and increases hypothalamic NPY mRNA expression (76).
Although, ghrelin has potent actions on appetite, ghrelin null mice have
normal appetite and body weight whenfed a standard diet however do
resist diet-induced obesity (77). This may be due to up-regulation of
alternative systems controlling appetite or perhaps ghrelin has only short
term effects on food intake, playing a smaller role in the overall
regulation of appetite.
(Figure5)
http://www.chemicalbook.com/ChemicalProductProperty_EN_CB124063
8.htm

30
6.2.Anorectic peripheral peptides:
6.2.1.Cholecystokinin (CCK):
CCK was the first gut hormone demonstrated to have an effect on food
intake. CCK is released post-prandially and in addition to local effects
within the gut, inhibits food intake in rodents and humans (78,79). CCK1
receptor knockout rats and intraperitoneal delivery of CCK1 antagonists
results in obesity, partly due to hyperphagia (80). The anorectic effects of
peripherally administered CCK are thought to be mediated via CCK 1
receptors on vagal afferent fibres that relay to the brainstem.
Interestingly, intraperitoneal CCK administration also increases c-fos
expression in the DMN and PVN of the hypothalamus (81). Direct
administration of CCK into the DMN decreases food intake and down-
regulates NPY gene expression (81).
Cholecystokinin (CCK) is a gut peptide that has long been established to
act as a postprandial satiety signal (82).It is released into the circulation
from enteroendocrine cells of the duodenum and jejunum in response to
fatty acids. CCK acts at receptors on peripheral vagal afferent terminals,
which transmit signal to appetite centers, such as the nucleus of the
solitary tract, contained within the brainstem. Peripheral administration
of CCK also activates mouse POMC neurons in the nucleus of the
solitary tracts with signaling via MC4Rs in this region appearing to be
crucial in bringing about the satiety effects of CCK. This peptide is
ineffective in reducing food intake in mice lacking MC4R and in mice in
which brainstem melanocortin receptorsare blocked pharmacologically
(83).hus in addition to integrating long-term adipostatic signals like

31
leptin, the melanocortin system may also be important in integrating
short-term gut-derived satiety signals.
(Figure6)
http://www.pharmacology2000.com/Central/Opioids/opioidiv3.htm
6.2.2. Leptin:
Leptin (also termed OB protein), a product of leptin gene (Lep(ob) was
discovered in 1994 by Friedman and colleagues. It is a protein of
molecular weight 18,000, containing a signal sequence which is cleaved
to produce the mature hormone of molecular weight 16,000 (84).Initial
studies suggested that leptin was only synthesized by the White adipose
tissue, but it is now recognized that the hormone is produced in several
other sites like brown adipose tissue, stomach, placenta, mammary gland,
ovarian follicles and certain fetal organs such as heart and bone or
cartilage and perhaps even the brain (85,86,87).
Circulating leptin is transported across the blood– brain barrier via a
saturable process (88).egulation of transport may be an important
modulator of the effects of leptin on food intake. Starvation reduces

32
transport, whereas refeeding increases the transport of leptin across the
blood–brain barrier (89).
Production of leptin correlates positively with adipose tissue mass (90).
Independent of the adiposity leptin levels are higher in women than in
men (91).Leptin has a dual regulation in human physiology. During the
periods of weight maintenance, when energy intake and output are equal,
leptin levels reflect total body fat mass. However, in conditions of
negative (weight loss programs) and positive(weight-gain programs)
energy balances the dynamic changes in plasma leptin concentration
function as a sensor of energy imbalance and influences the efferent
energy regulation pathways (91).Rising levels of leptin signal the brain
that excess energy is being stored, and this signal brings about
adaptations of decreased appetite and increased energy expenditure that
resist obesity. About 5% of obese populations can be regarded as
‘‘relatively’’ leptin deficient which could benefit from leptin therapy (91).

33
(Figure7)
http://www.chemicalbook.com/ChemicalProductProperty_EN_CB3304602.htm
 What Regulates Leptin Secretion?
The adipocyte is not a classical endocrine cell and leptin is not stored in
typical endocrine secretory granules. The amount of leptin produced by
an adipocyte appears to be regulated at the transcriptional level but also
at the levels of translation, storage, turnover, and secretion (92).. Leptin
levels do show some diurnal variation, but this appears to be entrained
by meal times in rodents. Insulin and glucocorticoids positively regulate
leptin production whereas agents that increase cAMP levels in the
adipocyte, such as β adrenergic agonists, suppress leptin production(93).
The marked sexual dimorphism in plasma levels(much higher in females
than males) is, at least in part, explained by a suppressive effect of
androgens on leptin production. The precise mechanisms whereby
increased fat stores are signaled to the adipose tissue mass to produce
more leptin remains mysterious, and progress has been impeded by very

34
low levels of leptin made in the otherwise very useful adipocyte cell lines
in which much adipocyte cell biology has been established.
6.2.3.Peptide YY (PYY):
Peptide YY (PYY) is a 36 amino acid peptide secreted from the endocrine
L cells of the gut. Circulating PYY levels are low in the fasting state and
rapidly increase post prandially when two forms, PYY1–36 and PYY3–36,
are released into the circulation. Both peptides have local effects on gut
motility and both have the ability to increase food intake if administered
directly into the cerebrospinal fluid of animals. In contrast, peripherally
administered PYY3–36 can reduce food intake (82). Like leptin, the
appetite-suppressing effectsof PYY3–36 were initially thought to be
mediated indirectly through the central melanocortin system. However,
this appears not to be the case as a disrupted melancortinergic system
still permits the full anorexigenic effects of PYY3–36(94). Some groups
have reported difficulty in reliably reproducing the anorexigenic effects
of PYY3–36,(95) a phenomenon that may reflect the influence of
environmental stimuli on the ability of the animals to respond. It has been
suggested that the inhibition of food intake by PYY3–36 is dependent, at
least in part, on the induction of an aversive response. (96)
In humans, PYY3–36 levels are elevated in many disease states that are
characterized by weight loss. Overweight subjects have been reported to
have a relative deficiency of postprandial PYY3–36 release associated
with reduced satiety(97) and bariatric surgery results in an exaggerated
postprandial PYY3–36 surge, potentially explaining the effectiveness of
such surgery in maintaining a prolonged reduction in postoperative
weight(98).. Whether or not PYY3–36 is a true endogenous physiological

35
regulator of food intake, longterm trials of PYY3–36 as an antiobesity
agent are ongoing, and the results are awaited with great interest.
(Figure8)
http://www.tocris.com/dispprod.php?ItemId=54383#.UbS0FqKLC9o

36
6.2.4. Amylin:
Amylin consisting of 37 amino acids, also known as islet amyloid
polypeptide was identified in 1987 (99). Amylin is a member of a family
of structurally related peptides, which includes calcitonin gene-related
peptide (CGRP) and calcitonin (CT). In mammals, amylin is co-released
with insulin from pancreatic b-cells in response to food intake and has an
anorectic effect (100). Amylin seems to decrease food intake through both
central and peripheral mechanisms and indirectly by slowing gastric
emptying. The mean basal amylin concentration is higher in obese than in
lean human subjects. Amylin and CCK-8 have been reported to reduce
food intake in rodents when given centrally as well as peripherally (100).
One mechanism by which amylin appears to reduce food intake is by
augmenting the actions of other peptides such as CCK, glucagon, and
bombesin, all of which also increase amylin secretion. However, the CCK
antagonists failed attenuate amylin’s reduction of food intake, suggesting
that amylin does not produce its effect through the release of CCK (101).
Instead it appears to be the converse that the anorectic effects of CCK
and bombesin depend partly on the presence of amylin or the calcitonin
gene -related peptide (CGRP) (102).
There is evidence that amylin may also exert its effects through
serotonergic, histaminergic, and dopaminergic systems. Amylin may
induce anorexia through its effect on brain serotonin by increasing the
transport of the precursor tryptophan into the brain (2), to inhibit feeding
by serotonin action in the paraventricular nucleus.

37
In animal and human studies, it has been found that amylin delays gastric
emptying and decreases food intake. Obese subjects exhibit
hyperamylinemia, and their elevated amylin levels may cause down-
regulation of amylin receptors and lessen the impact of postprandial
amylin secretion on satiety and gastric emptying. Obese subjects often
experience hyperglycemia and increased corticosteroid secretion (103),
both of which enhance amylin secretion in response to a meal, which
could lead to amylin resistance. Amylin administration to obese
individuals may have the potential to promote weight loss by delaying
gastric emptying and inhibiting food intake, and overcoming resistance at
the target tissues.
(Figure9)
http://www.phoenixpeptide.com/catalog/pnxfoget.php?id=pnxnews_000000303&title
=Compound&sum=Function

38
6.2.5. Insulin:
Insulin is a major metabolic hormone produced by the pancreas and the
first adiposity signal to be described (104). Levels of plasma insulin vary
directly with changes in adiposity (105) so that plasma insulin increases
at times of positive energy balance and decreases at times of negative
energy balance (106).
Recent findings suggest that little or no insulin is produced in the brain
itself (107,108). Once insulin enters the brain, it acts as an anorexigenic
signal (109). The insulin receptor is composed of an extracellular β -
subunit which binds insulin, and an intracellular β-subunit which
transduces the signal and has intrinsic tyrosine kinase activity.
(Figure10)
http://www.bio.davidson.edu/Courses/Molbio/MolStudents/spring2010/H
olzwarth/Insulin.html

39
6.2.6.Bombesin:
Bombesin is a 14-amino acid peptide(110)originally isolated from the
skin of the oriental fire-bellied toad (Bombina orientalis). It has two
known homologs in mammals called neuromedin B and gastrin-releasing
peptide. It stimulates gastrin release from G cells. It activates three
different G-protein-coupled receptors known as BBR1, -2, and -3(111).It
also activates these receptors in the brain. Together with cholecystokinin,
it is the second major source of negative feedback signals that stop eating
behaviour (112).
Bombesin is also a tumor marker for small cell carcinoma of lung,
gastric cancer, and neuroblastoma (113).
(Figure11)
http://www.chemicalbook.com/ChemicalProductProperty_EN_CB215234
5.htm

40
6.3.Anorectic neuropeptides secreted by hypothalamus:
6.3.1. Glucagon like peptide-1 (GLP-1):
The pre-pro-glucagon gene is widely expressed in the enteroendocrine L
cells of the intestine, pancreas and brainstem. It is cleaved by pro-
hormone convertases 1 and 2 to produce mainly glucagon in the
pancreas, and GLP-1, GLP-2 and oxyntomodulin in the CNS and
intestine.
GLP-1 is released into the circulation following a meal in proportion to
the calories consumed and acts via the vagus nerve to inhibit food intake
(54). Central administration of GLP-1 to rats inhibits food intake and
activates c-fos expression in the ARC, amygdala and PVN (114,115).
GLP-1 receptor mRNA is densely expressed in the ARC and over 60%
appears to be co-localized with POMC neurons (116). Peripherally
injected GLP-1 also induces expression of c-fos in the ARC and has an
anorectic effect (117). However, this is thought to be mediated, in part,
via the vagus nerve since vagotomy or ablation of the brainstem-
hypothalamus pathways attenuates the anorectic effect of GLP-1 (117).

41
Glucagon-like peptide-1 (GLP-1) is a peptide product of the pro
glucagon gene, released from the L cells of the small intestine in response
to food ingestion (118) .GLP-1 is a potent inducer of glucose-dependent
insulin release. This has lead to the development of GLP-1 agonists that
have clinical utility in the treatment of type 2 diabetes mellitus (118). GLP-
1 can also influence food intake with the GLP-1 analog exenatide,
capable of lowering both blood glucose and body weight in obese type 2
diabetic subjects. The effects on body weight may be as a result of
induction of satiety via inhibition of gastric emptying, but there is also
evidence that GLP-1 can influence feeding behavior by acting at the
nucleus of the solitary tract in the brainstem and the para ventricular
nucleus of the hypothalamus (82).
(Figure12)
http://www.guidechem.com/cas-161/161748-29-4.html

42
5.3. 2.Serotonin:
Serotonin (5-HT) originates from the midbrain dorsal raphe nucleus and
projects to the hypothalamus, including the PVN and the VMH. It is an
important modulator of many developmental, behavioral, and
physiological processes, including sleep, appetite, temperature
regulation, pain perception, and motor activity(119). Specifically, 5-HT
drugs reduce appetite prior to and after the consumption of fixed caloric
loads, and reduce premeal appetite and caloric intake at ad libitum
meals. Clinically significant weight loss over a year or more can be
produced by both D-fenfluramine and sibutramine treatment, but
apparently not by the SSRI fluoxetine.
(Figure13)
http://en.wikipedia.org/wiki/File:Serotonin-2D-skeletal.svg

43
6.4. Orexigenic neuropeptides secreted by hypothalamus:
6.4.1 Melanin-Concentrating Hormone:
Melanin-concentrating hormone (MCH) is an Orexigenic cyclic 19 amino
acid neuro peptide. It is cleaved from its precursor pre pro-MCH (pp
MCH) along with several other neuro peptides whose roles are not fully
defined (120).
The melanin-concentrating hormone system is thought to play a role in
arousal in correlation with specific goal oriented behaviors such as
feeding or reproduction (121). Several lines of investigation suggest that
the hypothalamic MCH regulates body weight in mammals. Obese mice
lacking functional leptin over express the MCH message in the fed or
fasted state. Acute Intra cerebro ventricular injection of MCH increases
energy intake in rats and decreases energy expenditure. On the other
hand, the MCH- or MCH-1R-deficient mice showed the resistance to
high-fat diet induced obesity (122). Moreover, MCH-transgenic mice
exhibit obese syndromes when fed on high fat diet.
Non-peptide antagonists for MCH-1R prevented the high-fat diet-induced
obesity, and possess anti-anxiety and antidepressant effect. These finding
indicate the involvement of MCH in the development of obesity, memory
and emotion. MCH receptor antagonist might be useful for the treatment
of obese syndrome including psychological disorder-related obesity (123,
124, 125, 126).

44
6.4.2.Neuropeptide Y:
Neuropeptide Y (NPY) contains 36 amino acid residues, including a
tyrosine at each end (hence ‘Y’, the code for Tyrosine) (127). NPY is one
of the most abundant peptides of the hypothalamus (128) and one of the
most potent orexigenic factors (129,130). It has been functionally
implicated in feeding behavior, cardiovascular regulation, and control of
neuroendocrine axes, affective disorders, seizures, and memory retention
(131). The ARC is the major site of expression for NPY within neurons in
the hypothalamus that project to PVN, DMH, LHA, and other
hypothalamic sites. Although NPY can produce diverse effects on
behavior and other functions, its most noticeable effect is the stimulation
of feeding after central administration (132). When administered intra
cerebro ventricularly (ICV) in rats, it produces a powerful and prolonged
increase in food intake (133). When administered chronically, NPY
produces hyperphagia, decreased thermogenesis and obesity (134). NPY
gene expression in the hypothalamus is found to be increased compared
to controls in many different rodent models of altered feeding (135,136).
NPY synthesis in the ARC and its release into the PVN, the most
abundant projection, are regulated by afferent signals such as leptin,
insulin (both inhibitory), and glucocorticoids (stimulatory). The NPY
neurons are potential hypothalamic targets for leptin and as discussed
later, inhibition of the synthesis (probably release) of NPY seems to
partly explain the ability of leptin to induce hypophagia and weight loss.
Insulin receptors are expressed in the mediobasal hypothalamus, and
median eminence, and insulin has been shown to inhibit NPY synthesis
and secretion in the PVN: however, it is not clear whether insulin

45
receptors are actually carried by the NPY neurons or by the neurons that
impinge on them (137,138). NPY synthesis and secretion are all up-
regulated in models of energy deficiency or increased metabolic demand
such as starvation, insulin-dependent diabetes mellitus, lactation and
physical exercise (132).
The NPY neurons that are activated by fasting are the neurons that
express the long form of the leptin receptor (139). A primary
physiological role of the ARC NPY neurons may thus be to restore
normal energy balance and body fat stores under conditions of energy
deficit, the signals of which are falling leptin and/or insulin occurring in
these conditions. By contrast, dietary obesity induced by voluntary over-
eating of highly palatable diet is not accompanied by obvious increases
in the activity of ARC NPY neurons. Indeed there is some evidence that
their activity may be inhibited thus attempting to restrain overeating
palatable food (140).
(Figure14)
http://www.chemblink.com/products/90880-35-6.htm

46
6.4.3. Orexins:
Orexins were originally identified as peptides produced selectively in the
lateral hypothalamus(141) .Central administration of orexin appeared to
increase food intake in mice leading to the initial viewthat the principal
function of orexins was the control of food intake. However, subsequent
studies suggest that orexins play a more important role in the
maintenance of alertness with genetic or acquired deficiency of orexin
signaling resulting in narcolepsy(142) . A possible link with the leptin
and the adipostatic pathways remains in that leptin administration
decreases orexin expression whereas fasting increases orexin mRNA
levels(143).
Orexin may also play a role as a peripheral hormone involved in energy
homeostasis. Orexin neurons, expressing both orexin and leptin
receptors, have been identified in the gastrointestinal tract, and appear to
be activated during starvation (144). Orexin is also expressed in the
endocrine cells in the gastric mucosa, intestine and pancreas (144) and
peripheral administration increases blood insulin levels (145).
(Figure15)

47
http://www.chemicalbook.com/ChemicalProductProperty_EN_CB9355020.htm
6.4.4 Agouti-related peptide:
AGRP is 132-amino acid peptide that has generated intense interest
because of evidence of its role in the regulation of feeding and body
weight (146). Like NPY, expression of AGRP is up-regulated in leptin
deficiency due to fasting or mutation. Chronic administration of AGRP in
rodents has been shown to cause sustained hyperphagia and leads to
obesity (147).
6.4.5Galanin:
Galanin is a neuropeptide which is not a member of any known family of
neuropeptides, despite repeated efforts to discover related peptides. It is a
29 amino acid C-terminally amidated (30 amino acid, non-amidated in
humans), highly conserved but unique neuroendocrine peptide originally
isolated from intestine. The first 14 AA are fully conserved in almost all
species. The first 16 N-terminal amino acids appear to contain
galaninagonist activity on increasing food consumption (148). Galanin is
found in the brain and the gut. It modulates a variety of physiological
processes including cognition/memory, sensory/pain processing,
neurotransmitter/ hormone secretion, and feeding behavior (149,150).
Acute central administration of galanin has been reported to increase fat
consumption. One of the studies has shown that repeated central
infusions of galanin stimulates daytime intake of both diets, they failed to
increase total daily energy intake or body weight in the rat (151).

48
(Figure16)
http://www.lookchem.com/cas-160/160525-09-7.html
6.5. Oxyntomodulin:
Like GLP-1, oxyntomodulin is secreted from intestinal L cells post-
prandially and reduces food intake when administered peripherally or
ICV to rodents (152). Peripheral administration of oxyntomodulin
activates c-fos expression in the ARC and its anorectic effects can be
blocked through the use of a GLP-1 antagonist (152). As a member of the
secretin glucagon family of peptides, oxyntomodulin differs in producing
a stronger inhibition of food intake than other members and has an
anorectic action disproportionate to its binding to the GLP-1 receptor
suggesting the possibility of an additional mode of action.
Another product of the tissue-specific differential cleavage of
proglucagon, OXM, is co-secreted with GLP-1 and PYY3–36 into the
circulation by intestinal L-cells after nutrient ingestion (153). OXM is a
satiety signal and administration reduces energy intake in both rodents
and humans (154–158). Indeed, preprandial subcutaneous administration
of OXM to overweight and obese humans over a 4-week period resulted
in a significant reduction in body weight of 2.3 kg, compared with 0.5 kg
for the placebo arm (185). In addition, OXM has been found to have a

49
beneficial effect on energy usage, in that it increased activity levels back
toward normal in overweight and obese volunteers (159). Oxyntomodulin
administration was well tolerated in these studies. Longer-term trials are
now required to determine whether its beneficial combination of
properties can be sustained. Like GLP-1, OXM is inactivated in large
part by DPP-IV, and its advancement as a clinically useful treatment will
be reliant on the development of a breakdown-resistant analog. In the
process of developing novel analogs of oxyntomodulin for the treatment
of obesity.
6.6.Pancreatic polypeptide (PP):
The panorectic gut hormone PP is released from the pancreas into the
circulation after a meal and like PYY, is released in proportion to
calories ingested. Peripheral injection of PP to rodents and humans
reduces food intake (160,161). Peripheral PP administration activates
neurons in the area postrema of the brainstem, an area with a high
density of Y4 receptors and reduces hypothalamic NPY and orexin mRNA
expression (160). Like PYY, the reduction of food intake by
intraperitoneal PP is abolished by vagotomy in rodents (160).
The role of pancreatic polypeptide in the regulation of energy balance is
unclear. Studies have shown that circulating levels are reduced in the
context of obesity, and there is a reduced second phase release after a
meal (162), whereas in anorexic patients, levels are elevated (163).
However, these findings have not been universally replicated (164,165).
PP reduces food intake when administered to rodents and humans(166–
168). It remains to be evaluated whether this effect is preserved in obese

50
humans. Work in individuals with Prader-Willi syndrome, characterized
by overeating and morbid obesity, is encouraging (169), but not
necessarily applicable to the more general nonsyndromic obese
population. However, the observation that a single infusion of pancreatic
polypeptide caused a measurable effect on food intake as long as 24 h
afterward in normal-weight volunteers (168) suggests that pancreatic
polypeptide may have potential as a long-term suppressor of appetite.
(Figure17)
http://www.chemicalbook.com.cn/ChemicalProductProperty_EN_CB9426108.htm

51
7.The Central Effects of Thyroid Hormones on Appetite:
7.1. Introduction:
Obesity, its complications, and the associated mortality are major public
health issues worldwide. The major central nervous system (CNS) areas
important in the regulation of appetite are the hypothalamus and
brainstem. The hypothalamus interprets and integrates afferent signals
from the periphery and that regulate food intake and energy expenditure.
brainstem to modulate efferent signals Neural and hormonal peripheral
signals communicate information including acute nutritional states and
energy stores. The hypothalamus is subdivided into a number of
interconnecting nuclei, including the paraventricular nucleus (PVN), the
ventromedial nucleus (VMN), and the arcuate nucleus(ARC), which are
particularly important in regulating energy homeostasis. The ARC is
located near the median eminence, where the blood-brain barrier is
incomplete, and is thus well positioned to respond to circulating factors
involved in appetite and food intake [170].
Recent evidence suggests that thyroid hormones may access the ARC and
other regions of the hypothalamus to regulate appetite (Figure 18). It is
well established that the hypothalamic-pituitary thyroid(HPT) axis
regulates body weight. Thyroid hormones are known to effect metabolic
rate. Thyroid dysfunction can have clinically significant consequences on
appetite and body weight. Hypothyroidism classically causes reduced
basal energy expenditure [171] with weight gain[172, 173]. Conversely,
hyperthyroidism increases energy expenditure and reduces body weight
[174–176]. Traditionally, it has been assumed that it is this reduced body
weight that drives the hyperphagia that can be a presenting feature in

52
hyperthyroidism. However, recent evidence suggests that the HPT axis
may play a direct role in the hypothalamic regulation of appetite,
independent of effects on energy expenditure. Classically, hypothalamic
thyrotropin-releasing hormone (TRH) stimulates thyroid-stimulating
hormone TSH) release from the anterior pituitary gland, which then
stimulates the release of both thyroid hormones, triiodothyronine (T3)
and thyroxine (T4). Reports suggest that all of these signalling molecules
can directly influence food intake [177–180]. Improved understanding of
the role of the HPT axis and thyroid hormone in appetite may identify
new targets for anti obesity agents.
7.1.2. Effects of Thyroid Hormones on Food Intake:
There are well-characterised effects of fasting on hypothalamic TRH
expression. This is primarily thought to down regulate the HPT axis in
periods of limited food availability, thus reducing food intake. However,
TRH has been reported to have direct anorectic effects, suggesting it may
regulate food intake independent of effects on the HPT axis. In rodents,
central administration of TRH reduces food intake[177, 181, 182];
similar effects on food intake are seen following peripheral
administration [183].
TSH has also been shown to reduce food intake when injected centrally
into rats [177]. There is evidence that TSH from the pars tuberalis is
involved in the photoperiodic response in birds and rodents, and it is thus
possible that TSH is involved with the seasonal alterations in food intake
and body weight that occur in some species [184–186].

53
The hyperphagia associated with hyperthyroidism may be a result of
thyroid hormones acting directly on CNS appetite circuits. T3 directly
stimulates food intake at the level of the hypothalamus. In rodent models,
peripheral and central hypothalamic administration of T3 increases food
intake [178–180].
There are several mechanisms postulated to mediate the orexigenic
effects of thyroid hormones. The ARC contains two distinct energy
homeostasis-regulating neuronal populations. One subpopulation
expresses the proopiomelanocortin(POMC) gene which codes for the
anorectic neuropeptide alpha-melanocyte-stimulating hormone(α-MSH).
The other expresses the orexigenic factors neuropeptide Y (NPY) and
agouti-related protein (AgRP). It has been reported that peripheral
administration of T3 increases hypothalamic NPY mRNA and that
intracerebroventricular(ICV) administration of a NPY Y1 receptor
antagonist blunts T3 induced hyperphagia, suggesting that T3 may
increase appetite via NPY [179]. T3 administration was also reported
toalso reduce hypothalamic POMC expression [179]. Another study did
not detect changes in hypothalamic neuropeptide expression in response
to peripheral administration of T3 though thismay reflect the different
doses of T3 administered[178].

54
(table 4)
However, the effects of thyroid hormones on food intake may not be
mediated directly by the ARC. Direct administration of T3 into the VMN
but not the ARC increases food intake in rats [178]. As appetite
regulating circuits in the ARC are known to be altered by changes in the
HPT, there may be an indirect effect of the ARC via the VMN allowing
intra-VMN T3 to increase food intake. In keeping with this, there are
excitatory inputs into POMC neurons that originate in the VMN [187].

55
(Figure 18)
(Figure 18): Schematic diagram of central appetite regulation. T3 can
access the hypothalamus and brainstem via the incomplete blood brain
barrier. PVN: paraventricular nucleus; ARC: arcuate nucleus; VMN:
ventromedial nucleus; BBB: blood-brain barrier; T3: triiodothyronine;
POMC: Pro-opiomelanocortin; NPY: neuropeptide Y; AgRP: agouti-
related protein; BDNF: brain-derived neurotrophic factor; HPT:
hypothalamic-pituitary thyroid; SNS: sympathetic nervous system.
7.1.3 Effects of Nutritional State on Thyroid Hormones:
Reduction in TRH in response to fasting may be important as TRH is seen
to have a direct anorectic effect when injected into the hypothalamus
[182]. It is possible there are distinct TRH neuronal populations
regulating the HPT axis and regulating appetite.
In periods of limited food availability, there is central downregulation of
the HPT axis. Serum T4 and T3 levels fall during fasting in humans [188]

56
and rodents [189, 190]. As the majority of T3 in rodents comes from the
thyroid gland, it is thought food deprivation may result in a fall in the
release of T4 and T3. This is likely secondary to a reduction in
hypothalamic TRH expression, an effect that may be mediated by the
adipose hormone lepton.
(Figure19)
(Figure19): Effect of fasting on the hypothalamo-pituitary-thyroid axis.
PVN: paraventricular nucleus; ARC: arcuate nucleus; TRH: thyrotropin
releasing hormone; TSH: Thyroid-stimulating hormone; T3:
triiodothyronine; T4: thyroxine; POMC: Pro-opiomelanocortin; NPY:
neuropeptide Y; AgRP: agouti-related protein.

57
8.Growth Hormone (GH) secretion:
8.1. Introduction
Human growth hormone (GH) is a mixture of peptides, the major
physiologic and bio active component being a 22 kDa polypeptide chain
of 191 amino acids secreted by the anterior pituitary gland . In man GH is
secreted episodically in a pulsatile fashion. The main regulatory
hormones of GH are two hypothalamic peptide hormones: GH releasing
hormone (GHRH) a 44 amino-acid peptide required for the initiation of
GH pulses and somatostatin an inhibitory peptide which modulates the
amplitude of GH pulses. However, several brain transmitter pathways as
well as sleep and several other factors seem to be involved in GH
regulation, suppressing or stimulating GH release by influencing GHRH
or somatostatin .
8.2.Metabolic and nutritional factors:
8.2.1Glucose:
An impaired GH response to hypoglycaemia is well documented in
obesity.[191-193] Moreover, recent studies performed with
hyperglycaemic clamp and oral glucose load have demonstrated that in
obese patients, contrary to normal subjects, hyperglycaemia does not
inhibit spontaneous[194] and stimulated (GHRH, arginine,
hexarelin)[195,196] GH secretion. On the contrary, the somatotropin
response to GHRH and arginine isphysiologically blunted by

58
administration of SRIH and of the cholinergic antagonist
pirenzepine.[196] These observations suggest an inability of hyper-
glycaemia to trigger hypothalamic SRIH release in obesity.
8.2.2.Insulin:
Obesity is characterized by fasting hyperinsulinemia and exaggerated
insulin release in response to a mixed and exaggerated insulin release in
response to a mixed meal or a glucose load.[197,198] and exaggerated
insulin release in response to a mixed meal or a glucose load.[197,198]
Experimental data support the existence of a negative feedback exerted
by circulating insulin on GH secretion. In normal subjects, a progressive
reduction of the GH response to hypoglycaemia[199] and GHRH[200]
has been observed with increasing insulin concentrations. The
mechanisms whereby insulin regulates GH release are not completely
clarified yet.
Insulin might act at both the hypothalamic and the pituitary level via its
multiple metabolic pathways. By binding to specific hypothalamic
receptors,[201 – 203] insulin could enhance the release of
catecholamines,[204,205] which in turn might stimulate SRIH discharge
via b-adrenergic receptors.[206]. However, in spite of the low number of
specific insulin receptors in normal pituitary cells,[207]an inhibition of
GH synthesis and release, along with a reduction of GH mRNA content in
somatotropes have been observed following exposure of these cells to
insulin in vitro.(208) Insulin might also regulate GH secretion through its
effects on aminoacid metabolism and ion transport. Lastly, insulin may
indirectly influence GH secretion by inhibition of IGFBP-1[209] and
hence by increasing the levels of free plasma IGF-I which negatively
feeds back on GH secretion. In spite of the above, the pathophysiological

59
relevance of hyperinsulinaemia in the GH hyposecretion of obesity is
challenged by the observation that GH secretion is normal in diseases
other than obesity associated with high insulin levels[210] and that in
obese subjects, normalization of serum insulin is not followed by
restoration of normal GH secretion.
8.2.3.Aminoacids:
GH is known to stimulate aminoacid uptake and protein synthesis.[211]
In turn, aminoacids participate in the regulation of GH release. Indeed,
high protein meals and administration of basic (arginine and ornithine)
and aromatic (tryptophan) aminoacids, stimulate GH secretion in normal
subjects,[212,213] probably because of a decrease in hypothalamic
SRIH.114 As mentioned above, an impairment of the GH response to
arginine, alone or combined with GHRH, is well documented in obesity.

60
9. Sex hormones:
The sex hormones estrogen, progesterone and androgens are important
modulators of food intake and energy balance in mammals(Fig.) (214),
where, as in most species, food intake and reproductive function are
closely linked. Sex hormones both interact with gastrointestinal peptides
and neurotransmitters to achieve central control of appetite and energy
expenditure, while also exerting direct peripheral action on adipocytes
(214).
Ovariectomy of rats increases food intake and, concomitantly, body
weight (215) and these effects can be reversed by restoring physiological
levels of estradiol (215). There is evidence that the effects of estradiol on
food intake are mediated via estrogen receptors in the hypothalamus
(e.g., the ARC and the PVN) and in the nucleus of the solitary tract in the
brain stem (215). However, itremains unclear whether estrogen receptor
(ER) _ or _ is involved(215–217). Moreover, these effects of estradiol
appear to involve several different mechanisms. For instance, estradiol
potentiates
the effect of the satiating CCK peptide released from the small intestine in
response to food intake (218,219), while attenuating the appetite-
stimulating potency of the gastric hormone ghrelin (220).
Furthermore, estradiol stimulates anorexigenic POMC/CART activity
and inhibits orexigenic NPY/AgRP neurons in the ARC (221,222). In
contrast to estrogen, progesterone itself does not significantly influence
feeding behaviour in ovariectomized rats, except when administered in
non-physiological, pharmacological doses (215). However, in the
presence of estrogen, progesterone does stimulate appetite and promote
weight gain (223). Testosterone stimulates appetite and eating in a
manner thought to be mediated centrally(214), selectively increasing the
number of meals, but not the size of each individual meal in rats (224).
Recently, neonatal exposure of female mice to testosterone was found to
enhance food intake and attenuate the expression of anorexigenic
POMC/CART neurons in the ARC of these same animals as adults (225).

61
(Figure20)
(Figure 20): Central neuroendocrinological control of appetite and food
intake. The hypothalamus plays a key role in the central regulation of
feeding, coordinating various neuroendocrinological inputs and signals
from absorbed nutrients to meet caloric needs and maintain energy
balance. In the arcuate nucleus of this organ, activation of POMC/CART
neurons inhibits, whereas activation of NPY/AGRP neurons stimulates
food intake. Circulating signals such as sex hormones, leptin, insulin and
ghrelin activate theses neurons through specific receptors. Cortico-limbic
systems, including the ventral tegmental area of the midbrain and the
nucleus accumbens in the striatum, are involved in the hedonic response
to food and modulate hypothalamic centers. The nucleus of the solitary
tract receives afferent signals from the gastrointestinal tract via the vagus
nerve and then transfers this information to the hypothalamus. AgRP,
agouti-related peptide; CART, cocaine-amphetamine-regulated
transcript; NPY, neuropeptide Y; POMC, pro-opiomelanocortin.

62
10.Treatment alternatives for obesity:
Reducing energy intake and exercise is the first line treatment for
inducing weight loss. However, most people find it difficult to lose weight
despite availability of widely available choice of diets and exercise
programmes, and even more difficult to maintain weight loss (226).
Current second-line treatments available are medications and surgery.
Currently, the only obesity treatment in clinical use that has shown
significant long-term weight loss is gastrointestinal Roux-en-Y bypass
surgery (226, 227). However, because of its complications, this
procedure is restricted to patients with morbid obesity. Post-surgical
weight loss is not caused by malabsorption, but is due to a loss of
appetite which may be secondary to elevated PYY and glucagon-like
peripheral peptides like oxyntomodulin, (228,229) and suppressed
ghrelin levels (230). This suggests that therapies based on these
hormones may be effective in the long term, without the need for surgical
intervention.
Anti-obesity medicines in clinical use have been fenfluramine, D-
fenfluramine and more recently sibutramine and orlistat. Only two drugs,
sibutramine and orlistat, are approved by the Food and Drug
Administration for long-term use (231). Sibutramine, a serotonin and
nor-adrenaline reuptake inhibitor, is recommended by the National
Institute of Clinical Excellence (NICE) for the treatment of obesity in
patients with a BMI of 30 kg/m2 or the presence of an obesity-related
disease and a BMI of over27 kg/m2 (232).

63
Orlistat, an inhibitor of pancreatic and gastrointestinal lipases, prevents
the absorption of approximately30% of dietary fat (233). Orlistat reduces
low density lipoprotein and cholesterol levels independent of reductions
in body weight, decreases the progression to a diabetic state, and leads to
better glycemic control in patients with diabetes. Side effects due to the
mode of action include oily spotting, liquid stools, fecal urgency or
incontinence, flatulence, and abdominal cramping. As orlistat may impair
the absorption of fat-soluble vitamins, a multivitamin supplement should
be taken 2 h before or after the medication (232).
These drugs have all been effective at reducing and controlling patients’
body weight, a clinical effect directly related to their hypophagic action.
However, all these drugs reduced food intake by reducing pre-meal
hunger and strengthening within meal satiation to reduce meal size. They
also prevent compensatory increases in meal number and reduce the
intake of snacks between meals which is an important trigger of caloric
over consumption (2).
The main focus in development of anorexigenic anti-obesity agents has
been on small molecule agents targeting known hypothalamic signaling
pathways, an approach that has repeatedly been hampered by safety
concerns. However, recently the focus has shifted to several islet and gut
peptide hormones targeting the hindbrain that play an important
physiological role in the regulation of food intake, meal size and
parandial satiation. The discovery of leptin and how it regulates other
peptides involved in energy homeostasis has opened a new spectrum for
drug development (2).

64
11.Surgery for the treatment of obesity:

65
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