According to the first law of thermodynamics,
energy can neither be created nor destroyed, but may be converted from one to
another form (
Fig. 1). When that energy or caloric intake equals the
energy output, an energy balance is maintained and the proportion of carbohydrates
(glycogen), protein and fat, averaging 0,75%, 20% and 15% of total body mass,
is preserved.
|
Fig.1.
Schematic representation of energy homeostasis and body weight regulation
in accordance with 1st law of thermodynamics. |
Obesity is one of the greatest threats to health because of the elevated risk
of type 2
diabetes mellitus, hypertension, cardiovascular diseases and
cancer. It can develop as overweight, when the body mass index (BMI) is between
25 and 29.9 kg/m
2 or as clinically defined form
of obesity, when BMI exceeds 30 kg/m
2. It is increasing
world-wide at an alarming rate in United States and in other industrialized
countries, raising by more than 30% over last decade to afflict on average 33%
of adults in United States, and 17% in UK and elsewhere including Poland (1).
In 1998 the World Health Organization (2) declared obesity as a chronic medical
disease because of the risk of serious complications, which prompted extensive
studies on its pathogenesis in order to apply appropriate treatment before the
dangerous disorders develop (3).
When energy (in the form of food) enters the body in greater quantities than are expended, the body weight increases, and most of the excess of energy is stored as fat. Therefore, excessive adiposity (obesity) is caused by energy intake in excess of energy output. Fat is stored mainly in adipocytes in subcutaneous tissue and in the intraperitoneal cavity, although the liver and other organs of the body may accumulate significant amounts of lipids in obese persons. It was believed previously that the number of adipocytes could increase substantially only during the infancy and childhood and that an excess of energy in children leads to "hyperplastic" obesity associated with increased number of adipocytes. In contrast, obesity in adults was thought to result from increased size of adipocytes leading to "hypertrophic" obesity. Recent studies have shown, however, that new adipocytes may differentiate from fibroblast-like preadipocytes at any period of life and the development of obesity in adults is accompanied by increased numbers, as well as increased size of adipocytes. Extremely obese persons may have as many as four times of adipocytes, than healthy controls, each obese subject containing twice as much lipids, as a lean person.
Hypothalamus centers and brain-gut axis in the pathomechanism of obesity
Generally, there are two systems that operate in the regulation of the quantity
of food intake; short-term regulation, that is concerned primarily with preventing
overeating at each meal, and long term regulation, which is primarily related
with the maintenance of normal quantities of energy stores in the form of fat
in the body (
Fig. 2). The regulation of body weight is based on homeostatic
system, however, this system is tuned toward weight gain and storage of fat,
whereas only few mechanisms exist that encourage weight loss (4). This regulatory
system evolved during thousands of years to cope with insufficient energy supply
rather than with a need to burn off an excess of calories. On an individual
long-term basis, energy balance is remarkable precise despite day-to-day variation
of food intake and energy expenditure.
|
Fig.2.
Schematic presentation of the short- and long-term regulation in appetite
and food intake. |
The possible mechanisms of eating disorders and obesity have been attributed
since the mid of 20 century to hypothalamus, the key region in central nervous
system (CNS) involved in feedback control of appetite and food intake though
other brain regions have also been implicated (
Fig. 3).
Nucleus tractus
solitarius (NTS) in the brain stem serves as gateway for neural signals
from the gastrointestinal tract to the hypothalamic feeding centers. Also the
amygdala, the
cortex prefrontalis, as well as the
area postrema
have been held responsible for feeding disorders and inadequate conservation
or storage of energy. In addition, both the
nucleus arcuatus (ARC) and
the
nucleus paraventricularis (PVN) are important centers in the control
of food intake (
Fig. 4). Early animal experiments with hypothalamic lesions
and post-mortem examinations in humans with morbid obesity led to a proposal
of the „dual center hypothesis“, postulating that ventromedial nuclei (VMN)
serve as the satiety center and the lateral hypothalamic area (LHA) - as the
feeding or hunger center (4) that when stimulated results in hyperphagia and
subsequently hypothalamic obesity (5, 6). It appears that the feeding center
is chronically (tonically) active and that its activity may be transiently inhibited
by activity of the satiety center occurring just after the ingestion of food.
The destruction of the feeding center in the lateral hypothalamus in animals
leads to anorexia with subsequent cachexia. Thus, through the neuronal network
systems in the lateral hypothalamus, the food intake is initiated as a basic
behavioral drive, while the ventro-medial hypothalamus is involved in the limitation
of food intake or satiety. In the short-term regulation of energy intake, the
structures in the brain control the intake of single meal regarding its volume,
energy content and duration. Following the food ingestion, the signals from
the receptors in oro-pharyngeal and gastric area are conveyed to NTS in brain
stem through afferent nerves. In addition to mechanical distention, the chemical
stimulation of receptors in gastro-intestinal mucosa and various hormones released
from the gastrointestinal mucosa by nutrients, contribute to the peripheral
signaling from gastrointestinal tract and pancreas with orexigenic as well as
anorexigenic properties (
Fig. 5).
|
Fig. 3. Feedback control of food intake including afferent vagal nerves activated by distention of the gastrointestinal tract and various gut hormones either stimulating (ghrelin) or inhibiting food intake (CCK, leptin, insulin etc.) |
|
Fig.4.
Model of central regulation of food intake in the hypothalamus. Ghrelin,
released from empty stomach activates NPY and AgRP containing neurons
in the ARC to stimulate food intake in LHA, while inhibiting POMC and
CART system responsible for the satiety. In contrast, leptin positively
regulates POMC and CART neurons in ARC to activate satiety and to inhibit
ghrelin-NPY/AgRP pathway. Peripheral neural (vagal) signals and various
gut hormones act on hypothalamic centers through the nucleus tractus
solitarius to affect food intake. |
|
Fig.5.
Schematic representation of neuro-humoral stimulation by cephalic, gastrointestinal
and adiposity signals in control of food (energy) intake. Solid lines
indicate stimulatory effects and dashes lines indicate inhibitory effects. |
With the discoveries of various enteropeptides and the recognition of the enteric
nervous system (ENS) and its two-way connections with CNS mainly
via
vagal nerves (7-9), the peripheral neurohormonal components have been implicated
in the short-term regulation of food (energy) intake (
Fig. 6). This reflects
an active regulatory process termed energy homeostasis promoting the stability
of the amount of body energy stored in the form of fat. It is of interest that
mice or rats are quite suitable models for studying the patho-mechanisms of
human obesity because substantial homology that exists across mammalian species
in the neurohormonal organization of the body weight-regulatory system (11).
|
Fig.6.
Gut peptides signaling through NPY/AgRP neurons to stimulate food intake in LHA or PVN or through POMC-a-MSH releasing neurons to induce satiety in medial hypothalamus. |
The hypothalamus with its key regions, including ARC, LHA and closely related
PVN, serving as the feeding or hunger center, VMN acting as the satiety center
and NTS conveying the peripheral signals, particularly from the gut to the feeding
centers, are implicated in appetitive behavior. Thus, CNS receives (through
NTS) numerous neural impulses and hormones from peripheral organs, especially
from the gastrointestinal mucosa, and fat tissue that are involved in short
and long-term coordination of feeding and energy expenditure in response to
constantly altered energy balance (
Fig. 6). The gut peptides signaling
to the hypothalamus act
via the ARC to mediate the appetite stimulation
(+) effect through the activation of neurons containing neuropeptide Y (NPY)
and Agouti-Related Peptide (AgRP) or appetite-inhibitory effects (-)
via
neurons containing the preopiomelanocortin (POMC)-derived
alpha-melanocyte
stimulating hormone (
alpha-MSH) and cocaine
and amphetamine regulated transcript (CART) peptide to hunger centers in the
LHA, the satiety center in PVN in the medial hypothalamus (16).
Peripheral orexigenic mechanisms
The major gastrointestinal hormone with potent orexigenic properties is ghrelin
(12) which has been identified in gastric ghrelin X/A cells characterized by
large eletrodense granules of P/D type in man and A-like type in rats (13).
It is a 28- amino acid peptide, primarily released by these endocrine cells
in empty stomach (
Fig. 7). Plasma concentration of ghrelin peaks under
fasting conditions before the meal and then levels off after meal to a nadir
to increase again after gastric emptying before next meal (14). The mechanisms
of ghrelin action on appetite and food intake is suggested to be primarily mediated
through peripheral input at the ARC and further spread to the NTS. Ghrelin exerts
growth hormone (GH)-releasing properties (15) and is involved in the hypothalamic
regulation of metabolic control and energy balance (12). Ghrelin serves as a
ligand for growth hormone secretagogue receptors (GHS-R). The primary hypothalamic
target for ghrelin are neurons in ARC that express and release NPY and AgRP
in the lateral hypothalamus and LHA to mediate orexigenic effect in the brain
(16, 17). It may also inhibit the neurons in the ARC that contain POMC-derivative
alpha-MSH that mediate the anorexigenic effect
in the PVN (9, 16, 18). An appetite stimulating action of ghrelin has been proven
in humans (19). Clinical implications of this have been applied to patients
with Prader-Willi syndrome that exhibit greatly increased circulating levels
of ghrelin (20, 21). Furthermore, gastric bypass surgery for morbid obesity
leads to the considerable weight loss (22, 23), pointing at a ghrelin as mediator
of altered energy balance. Peripherally in the gut, ghrelin was shown by us
to stimulate gastric acid secretion and gastrin release (24) and to exhibit
the gastro- and pancreato-protective activities against various irritants (25).
In addition, ghrelin was reported to exert a prokinetic effect on the small
bowel, where it stimulates activity front of the migrating motor complex (MMC)
through cholinergic mechanisms (26). It is of interest that food desire combined
with an increased gastric acid secretion occurs after intake of ethanol at low
concentration ("cocktail"), which appears to enhance the overexpression of ghrelin
in the oxyntic mucosa and an increase in plasma levels of this peptide, gastric
motility and gastric acid secretion (27). Thus, ghrelin seems to contribute
to the initiation of food intake and to stimulation in motilin-like fashion
of gastrointestinal motility.
|
Fig.7.
Schematic presentation of the release of ghrelin from the endocrine gastric
cells and of the actions of this peptides on appetite and other functions
including GH release, stimulation of cardiovascular system and metabolism. |
In addition to the initiation of food intake, exogenous ghrelin decreases the
release and action of leptin and
vice-versa exogenous leptin reduces
the plasma level of ghrelin (28). It has been proposed that leptin exerts a
negative regulatory effect on the release and action of ghrelin and that an
increase in ghrelin level induced by fasting or weight loss arises because of
the diminished inhibitory effect from leptin and probably also from PYY. This
may implay that weight-reducing effects of leptin are mediated not only by its
direct central action on hypothalamus but also through its peripheral inhibitory
effect on the release and action of ghrelin. According to our experience in
rats, the parenteral administration of ghrelin at a dose that raised plasma
hormone to the level observed under fasting conditions, significantly attenuates
plasma levels of leptin, while markedly increasing food intake. Immunoneutralizatrion
of circulating plasma ghrelin with specific IgG anti-ghrelin antibodies, causes
a marked increase in plasma leptin and decrease in food intake. In contrast,
exogenous leptin, at the dose (10 µg/kg ip) that raised plasma leptin to the
level occurring postprandially, reduced markedly plasma levels of ghrelin and
attenuated food intake and these effects can be reversed by the administration
of specific IgG anti-leptin antibodies (28). These results clearly support the
hypothesis that ghrelin negatively controls plasma release of leptin and
vice-versa
that leptin has a counter-regulatory influence on ghrelin release and action,
though the former effect appears to be much stronger than the later. This interaction
between ghrelin and leptin in control of food intake is called "argentinian
ghrelin-leptin tango" (
Fig. 8).
|
Fig.8.
Negative interactions of gut hormones, especially ghrelin and leptin,
on food intake. |
In addition to ghrelin, orexin A (OXA) and B (OXB), the novel neuropeptides were found to play the role in the stimulation of food intake and energy homeostasis (29). OXA has been detected in the mucosa and neuronal plexuses of the gastrointestinal tract and in the CNS, especially in LHA that is involved in the stimulation of food intake (30, 31). Plasma levels of OXA are increased during fasting in humans (32) and are lower in obese subjects than normal-weight people (33), suggesting that peripheral OXA modulates food intake as an orexigenic peptide (34). However, intravenous infusion of OXA in humans does not appear to induce any hunger-stimulating drive but increases gastric emptying (35).
Peripheral anorexigenic mechanisms
The postprandial satiety has been ascribed to numerous signaling molecules,
expressed and released in the gastrointestinal tract and also in hypothalamic
ARC, to inhibit food intake
via activation of the receptors on afferent
(mostly vagal) nerves stimulating the satiety center and inhibiting the feeding
center (9) (
Fig. 9). Among the anorexigenic peptides, the first recognized
inhibitor of food intake in rodents (36) and then in humans (37-40) was cholecystokinin
(CCK), the product of duodeno-jejunal endocrine I cells acting
via CCK
1
receptors on vagal afferent nerves. This hormone exists in the mucosa and circulation
in several molecular forms such as CCK-8, CCK-33, CCK-39 and CCK-58. All these
molecular forms derive from a single CCK gene through posttranslational processing
and have the same C-terminal five amino acid sequence. CCK was found not only
in the intestinal mucosa but also in peripheral nerves and in neurons of the
brain (41).
|
Fig.9.
Schematic presentation of the release and action of various gut and adipose tissue peptides on the ARC neurons affecting food intake. |
CCK is the likely candidate for the physiological mediation of short-term inhibition
of food intake. It cooperates with signals originating from the mechanoreceptors
of the gut that are generated by the distention of the gut and transmitted to
the brain through vagal afferents. This is in keeping with earlier findings
that sub-diaphragmatic vagotomy abolishes anorexigenic activity of exogenous
CCK (42) and, as we found it for the first time (36), and the blockage of CCK
1
receptors with loxiglumide abolishes the anorexigenic effects of both exogenous
and endogenous hormone. The clinical usefulness of CCK as an anti-obesity, appetite
reducing agent was found, however, to be transient due to the development of
tolerance to CCK and its analogs (43). Furthermore, even removal of gene for
CCK
1 receptors, (CCK
1
receptor knockout mouse) failed to increase the food intake, but resulted in
the lack of the sensitivity of these animals to anorexigenic action of exogenous
CCK (44). Since CCK only intermittently preserves its anorexigenic activity
between injections of exogenous CCK, compensatory overeating occurs, so it is
unlikely that this peptide could be useful in anti-obesity therapy.
Anorexigenic effects of adiposity factors
The control of body weight is actually limited to the control of adipose tissue
that not only plays a role in copious energy storage but also serves as thermal
isolator, protector of inner organs as well as a site of hormone secretion (aromatase).
With the discovery by Zhang
et al. in 1984 of leptin (45), a peripheral
active appetite inhibiting hormone produced by adipocytes and acting both
via
specific receptor (Ob-R) on afferent vagal nerves and directly on ARC neurons
enhancing satiety, raised a hope in progress in obesity therapy (44). Although
leptin inhibits expression of orexigenic NPY/AgPR hypothalamic neurons, while
stimulating anorexigenic POMC neurons in ARC (45), its practical therapeutical
application in fighting excessive appetite in obese people appears to be unjustified
because the majority of obese humans already exhibit high plasma levels of leptin,
proportional to the body fat storage, indicating their resistance to circulating
leptin (46). The mechanism of this is unknown but poor penetration of peripheral
leptin to hypothalamic regions due to reduced capillary transport system in
hypothalamic microcirculation could be responsible for its limited efficacy
as an anti-obesity drug (47). Leptin is produced not only in the adipose tissue
but also in the gastrointestinal tract, particularly in the stomach, where it
has been shown to protect the gastric mucosa against various topical irritants
and ulcerogens, acting, at least in part,
via enhancement of mucosal
blood flow due to increased production of nitric oxide (NO) caused by upregulation
of NO synthase as well as the activation of brain-gut axis pathways (48, 49).
Since leptin is released by excitation of vagal nerves by sham-feeding, that
operates entirely
via brain-gut axis (49), it may be assumed that gastroprotective
and hyperemic effects of leptin are centrally mediated, at least in part, by
the activation of sensory vagal fibers (50). This is supported by our finding
that the pretreatment of with neurotoxic dose of capsaicin abolished the gastroprotective
activity of leptin (51). Unfortunately, the effects of such treatment on appetite
reducing action of leptin have not been tested.
Leptin - insulin lipostat
Although there is rather low local expression of leptin in the stomach, probably
responsible for local antagonism of gastric release of ghrelin and named "leptin/ghrelin
tango" operating along the brain-gut axis (9, 52), leptin belongs together with
insulin to a "lipostat" substances that play a role in adiposity signaling (
Fig.
9). Insulin, like leptin, is thought to inhibit NPY/AgRP neurons in ARC
region of the hypothalamus and reduce food intake (53, 54). This is supported
by the observations that insulin applied intra-cerebro-ventricularly (icv) inhibits
food intake. Accordingly icv administration of insulin antibodies increased
food intake and body weight (53). Thus, leptin-like insulin, represents adiposity
signal inhibiting food intake by interacting with hypothalamic receptors activated
through POMC and CART neuronal pathways stimulating satiety center, and reducing
the activity of NPY/AgRP neurons driving the appetitive behavior.
Other anorexigenic peptides
This list of anorexigenic substances is long and includes numerous gut peptides
such as pancreatic polypeptide (PP), peptide-YY (PYY) and glucagon-like peptide-1
(GLP-1) (
Fig. 10). Two first peptides are 36 amino-acid long peptides
that act
via G-protein receptor subtypes-Y1, Y2, Y3, Y4, Y5 and Y6 mediating
the overlapping physiological actions of PP-family peptides. PP is primarily
expressed in the endocrine PP-cells of the pancreas. The amounts of PP released
depend upon the digestive state; the release is low when fasted and increases
during all phases of digestion (55, 56). The main stimulus of PP release is
the ingestion of protein and fatty meal. It has been demonstrated that PP is
released by other gut hormones such as ghrelin, motilin and secretin, but somatostatin
was shown to inhibit its release. PP exerts its effects through the specific
receptors (Y1-Y5) and exhibits inhibitory action on pancreatic secretion (55,
56) and gastrointestinal motility (57). As shown recently by Asakawa
et al.
(58) Katsumura
et al. (59), peripheral administration of PP attenuates food
intake and gastric emptying, while icv injection of PP increases food intake
and delays gastric emptying, but it is not excluded that PP effects on food
intake are secondary to changes of gastric emptying (59). Using transgenic technology
it has been shown that mice overexpressing PP exhibit a significant decrease
in total food intake (60). The reduction in appetite in those mice was associated
with a decreased rate of gastric emptying of solid meal. The anorexigenic activity
of PP was demonstrated in humans and PP was found not to develop tolerance.
Batterham
et al. (61) showed that PP infusion in humans reduces both appetite
and food intake. Such PP infusion had no significant influence on plasma concentrations
of ghrelin, PYY, GLP-1, leptin and insulin, suggesting that anorexigenic action
of PP is independent of changes in these hormones. PP is also released during
strenuous exercise and may, therefore, account for a reduced appetite following
the exercise (62). It is of interest that children with Prader-Willi syndrome,
which exhibit hyperphagia and obesity have a low level of plasma PP and infusion
of PP in those children leads to reduction in food intake (63).
|
Fig.10.
Neuro-hormonal factors originating from the gastrointestinal tract and stimulating or inhibiting satiety and gastric acid secretion through the activation of stimulatory or inhibitory afferent vagal nerves. |
PYY is another candidate for the short-term control of food intake (64, 65)
that originates from the L-cells in the ileal and colon mucosa following stimulation
by feeding, particularly when ingested nutrients, namely fatty acids, reach
the distal portion of the small bowel and colon (66). In addition to nutrients,
PYY also released by gastric acid, CCK, and by bile salts. It is of interest
that an intraduodenal meal increases plasma PYY even before nutrients reach
the PYY-containing cells in the ileum or colon. This suggests the release of
PYY through neural reflex, possibly mediated by the vagus. Plasma PYY levels
are increased by insulin-like growth factor 1 (IGF-1), bombesin, and calcitonin-gene-related
peptide and decreased by GLP-1. PYY is usually stored in endocrine cells of
intestinal mucosa as 36-amino-acid peptide (67), but in the blood circulation
it is converted into truncated form, PYY
3-36,
acting
via Y1, Y2, Y3 and Y5 receptors.
Early studies on the action of peripherally administered PYY demonstrated numerous
effects of this peptide on gastrointestinal tract. PYY delayed gastric emptying
and inhibited gastric and pancreatic secretion and gall-bladder emptying while
increasing ileal postprandial fluid and electrolyte absorption (67-69). Peripheral
PYY3-36, like PP, was reported to decrease appetite and to inhibit food intake
and weight loss in rodents and humans by inhibiting ARC expressions of NPY/AgPR
(70-72). In contrast, injections of PYY
3-36
into the third, lateral or fourth cerebral ventricle, the paraventricular nuclei
or the hippocampus in rodents potently stimulated food intake and feeding behavior
by enhancing expression of NPY/AgRP in neurons of ARC. The discrepancy between
peripheral and central administration of PYY on food intake has not been explained,
but Batterham
et al (72) proposed that it may be due to the activation
by this peptide of Y2 receptors in hypothalamic ARC neurons where the blood-brain
barrier is relatively permeable.
It is of interest that obese people have similar sensitivity to the appetite
inhibitory action of exogenous PYY
3-36 as lean
subjects indicating a lack of the resistance to the action of peptide. Since
tolerance did not develop with applications of PYY
3-36,
it is reasonable to assume that this peptide (similar to PP, but opposite to
leptin) has potential in long-term obesity therapy. The mechanisms of hunger
reduction in subjects treated with PYY is not clear but the finding of the reduction
in plasma preprandial ghrelin concentration suggests that the interaction between
these two gut peptides could contribute to the anorexigenic effect of PYY (
Fig.
10).
Glucagon-like peptide-1 (GLP-1) is produced and secreted by endocrine L-cells found in the ileal and colonic mucosa in response to food intake (73, 74). GLP-1 has received attention as being the chief contributor to ileal brake mechanisms of the upper gastrointestinal tract regarding gastric and pancreatic secretion and gastric emptying (75, 76). By slowing gastric emptying of a liquid or solid meal, GLP-1 reduces the postprandial demand of insulin to maintain euglycemia after a meal (77, 78). Accumulating evidence supports the notion that the effects of GLP-1 on gastrointestinal functions are mediated through its distinct receptors on vagal nerves both in animals and man (79-81).
In humans, GLP-1 was found to increase satiety and decrease food intake in normal-weight subjects, diabetes patients and obese subjects (82-85). As obese humans show lower circulating glucagon-like peptide-1 (GLP-1), similar to that of PYY, it has been thought that the resistance to this gut hormone contributes to the obesity. However, GLP-1 is an effective anorexigenic peptide, inhibiting effectively food intake, even after prolong administration, indicating that this peptide could be a physiological regulator of food intake. As obese subjects appear to display a more rapid gastric emptying of solids compared to normal weight subjects (86) and the natural increase in plasma GLP-1 is attenuated in obese subjects (86, 87), the smaller release of GLP in the obese subjects could cause less pronounced satiety of food intake, leading to earlier onset of the next meal. After jejuno-ileal bypass, the postprandial GLP-1 is enhanced concomitant with slower gastric emptying (87). This indicates that peripheral action of GLP-1 is important for the satiety and that it involves vagal nerves controlling gastric motor activity.
Oxyntomodulin (OXM) is produced by the same L-cells as GLP-1 in the distal portion of the gut and also in the brain (88, 89). It is a 37 amino acid peptide released after ingestion of meal and exerting various biological effects, including inhibition of gastric secretion and emptying, decrease in pancreatic secretion and stimulation of intestinal glucose uptake (89-91). Furthermore, it has been suggested to be involved in the short-term suppression of food intake in rats (90) and humans (91). The mechanism of anorexigenic action of OXM is not known but it may involve the suppression of plasma ghrelin levels (91). It is not clear whether OXM, acting through GLP-1 receptors will be effective in the decrease of appetite and food intake in obese subjects and this requires further studies.
Helicobacter pylori (H. pylori) infection and feeding behavior
Recently, gastric
H. pylori infection has been shown to affect expression
and release of leptin and ghrelin (92). The prevalence of
H. pylori infection
is about 60-80% of asymptomatic humans, but in all infected humans, it causes
active chronic gastritis, sometimes peptic ulcer (10-15%) or even cancer (2-5%).
Such an infection was found to be accompanied by an increase in plasma leptin
that normalized following eradication of
H. pylori (
Fig. 11).
The
H. pylori-induced rise in plasma leptin (49) could contribute to
the loss of appetite in infected patients. However, even more important than
the rise of leptin may be the fall in gastric expression and release of ghrelin,
as reported by Nwokolo
et al (94), confirming that indeed,
H. pylori
infection could be responsible for the loss of appetite, the decrease of food
intake and the growth retardation in children. The mechanism by which
H.
pylori infection leads to reduction in plasma ghrelin concentration is unknown,
but since leptin was shown to inhibit ghrelin expression, it is not excluded,
that the rise in plasma leptin that follows
H. pylori infection might
explain the decreased ghrelin release. Alternatively, the possibility exists
that hypergastrinemia that usually accompanies
H. pylori infection inhibits
the release of ghrelin and this is supported by the recent finding that eradication
of
H. pylori that caused an immediate suppression of plasma gastrin was
associated with a significant elevation in plasma ghrelin and restoration of
good appetite (95) (
Fig. 11).
|
Fig.11.
Effects of H. pylori infection on gastric leptin and ghrelin release
and action on hypothalamus and pituitary as well as food intake and body
weight. |
Current treatments
The recognition of obesity as chronic medical disease by World Health Organization
in 1998 (2) and co-morbid pathologies including cardiac diseases, type 2
diabetes
mellitus, hypertension and dyslipidemia or cancer, all should be considered,
when selecting the most appropriate treatment of obesity. Although morbid obesity
is a multi-genetic state in majority of patients, no gene therapy has so far
been successfully applied. The dietary restriction and the long therapy such
as the use of Orlistat, which interferes with gastric or pancreatic lipases
to reduce intestinal fat absorption or Subitramine to enhances central noradrenaline
or serotonine signalling to promote satiety and reduce appetite, result in rather
small weight loss and has to be limited to application during only 1-2 years.
The prolong use of certain gut peptides such as PYY
3-36
and GLP-1, seems to be rational, particularly, that the deficiency of these
peptides in obesity has been documented (95). The wider use of those agents
requires, however, the approval by reliable health protection authority.
The only therapy that provides transient or even permanent weight loss and prolong
suppression of appetite are various procedures of bariatric surgery, because
their relatively low cost, almost immediate improvement of co-morbid conditions
and obesity-related side-effects. These bariatric procedures include more or
less drastic restrictive operations, such as gastric bands of various types
but also more effective operations such as restrictive gastric and intestinal
procedures aiming at decreasing the amount of absorbed nutrients. It is of interest
that these procedures reverse the abnormal profile of gut hormone expression/release,
particularly of ghrelin, orexigenic peptide, while raising the deficient anorexigenic
peptides such as PYY
3-36, GLP-1 and leptin.
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