Ghrelin, a 28-amino residue peptide hormone, which is predominantly
derived from the stomach and circulating in the bloodstream was discovered in
1999 [27]. One year later, it has been reported that ghrelin promotes a positive
energy balance and increases fat mass in rodents [28]. These findings were
counterintuitive since ghrelin has been first described as a growth hormone
secretagogue and therefore believed to have lipolytic – if any – effects on fat
mass. Modern methods for in vivo body composition analysis using double-
X-ray absorptiometry (DEXA-scan) as well as nuclear magnetic resonance
(NMR), which were both specifically developed and adapted for rodent body
composition analysis, helped to unmask these impressive effects. But how,
by which mechanisms, could such a positive energy balance be generated
following ghrelin administration in rats and mice? Increased orexigenic drive
causing an increased ingestion of calories was an obvious explanation. However,
while central ghrelin administration markedly increased food intake, peripheral
administration of ghrelin did not seem to have orexigenic effects when
measured every 24 h. The discrete increase in food intake following peripheral
(i.p., s.c.) ghrelin administration can only be detected if food intake, i.e. after 1,
2 and 4 h, is carefully monitored, and appears more pronounced in male rodents,
on a standard chow and dependant from the rat strain used. A real-time food
intake monitoring system allows for several measurements every minute over
up to one week and therefore can unmask transient and discrete effects. The
so generated data also help to understand meal patterns, including number,
duration and caloric extent of each ‘meal’ in rodents. The discrete changes
in food intake following peripheral ghrelin administration, however, do not
seem sufficient to explain the easily reproducible and solid increase in body fat
mass occurring after i.p. or s.c. ghrelin administration. Ghrelin also increases
the respiratory quotient (reflecting decreased fat utilization and increased
derived from the stomach and circulating in the bloodstream was discovered in
1999 [27]. One year later, it has been reported that ghrelin promotes a positive
energy balance and increases fat mass in rodents [28]. These findings were
counterintuitive since ghrelin has been first described as a growth hormone
secretagogue and therefore believed to have lipolytic – if any – effects on fat
mass. Modern methods for in vivo body composition analysis using double-
X-ray absorptiometry (DEXA-scan) as well as nuclear magnetic resonance
(NMR), which were both specifically developed and adapted for rodent body
composition analysis, helped to unmask these impressive effects. But how,
by which mechanisms, could such a positive energy balance be generated
following ghrelin administration in rats and mice? Increased orexigenic drive
causing an increased ingestion of calories was an obvious explanation. However,
while central ghrelin administration markedly increased food intake, peripheral
administration of ghrelin did not seem to have orexigenic effects when
measured every 24 h. The discrete increase in food intake following peripheral
(i.p., s.c.) ghrelin administration can only be detected if food intake, i.e. after 1,
2 and 4 h, is carefully monitored, and appears more pronounced in male rodents,
on a standard chow and dependant from the rat strain used. A real-time food
intake monitoring system allows for several measurements every minute over
up to one week and therefore can unmask transient and discrete effects. The
so generated data also help to understand meal patterns, including number,
duration and caloric extent of each ‘meal’ in rodents. The discrete changes
in food intake following peripheral ghrelin administration, however, do not
seem sufficient to explain the easily reproducible and solid increase in body fat
mass occurring after i.p. or s.c. ghrelin administration. Ghrelin also increases
the respiratory quotient (reflecting decreased fat utilization and increased
carbohydrate utilization) and transiently (ca. 120min after ghrelin injection)
decreases energy expenditure as measured with an indirect calorimeter. This
decreased energy expenditure following ghrelin administration can however
not be verified if exclusively changes over 12 or 24 h are analyzed. Still, the
complete extent of ghrelin induced obesity can not be explained, which
(in part) may be due to the fact the sensitivity with which indirect rodent
calorimetry can detect energy expenditure is still unsatisfactory. Additional
methods such as measurement of changes in body core temperature or spontaneous
locomotor activity can be employed to obtain a more complete collection
of data on ghrelin’s effects on energy balance in rodents. Interestingly,
ghrelin seems to decrease body core temperature by more than 1 C, an effect
possibly reflecting a ghrelin induced impairment of thermogenesis. This effect
becomes more pronounced in rodents exposed to 4 C (climate chambers). At
these challenging conditions body core temperature decreases by 2–3 C following
ghrelin administration, while saline injected controls are able to maintain
their body core temperature (as measured by intraperitoneally implanted
transponders). Either a two-dimensional infrared light beam system or the
same implantable transponders used for temperature measurement can be used
to detect changes in spontaneous locomotor acitivity following ghrelin administration
– yet another parameter, which influences the net outcome of energy
balance and eventually the amount of fat mass accumulated over time. Ghrelin
decreases locomotor activity but these effects can only be observed following
intracerebroventricular (i.c.v.) ghrelin administration, while peripheral ghrelin
injections do not seem to significantly change spontaneous locomotor activity.
Last but not least, not all calories ingested are absorbed and used. Therefore,
a simultaneous analysis of the metabolic efficiency of the rodent model under
the investigated conditions and influences is mandatory. For these purposes
metabolic cages are used to separately collect feces and urine while measuring
food intake and body weight. Later, caloric content of feces and urine are measured
in a bomb calorimeter to detect changes in metabolic efficiency or
intestinal absorption following the administration of a drug or the deletion or
overexpression of a gene in rodent models. For these purposes of accurately
measuring energy balance in rodent models, it is also advantageous to precisely
compose rodent chow with a distinct percentage of fat, protein and
carbohydrates and to then provide equally shaped pellets, which can be
used to compare different diets. While (at least in rodents) stomach-derived
ghrelin might not represent the ‘hunger-’hormone, the above described observations
indicate that ghrelin triggers a positive energy balance via a combination
of effects on physiological mechanisms, eventually increasing fat mass.
decreases energy expenditure as measured with an indirect calorimeter. This
decreased energy expenditure following ghrelin administration can however
not be verified if exclusively changes over 12 or 24 h are analyzed. Still, the
complete extent of ghrelin induced obesity can not be explained, which
(in part) may be due to the fact the sensitivity with which indirect rodent
calorimetry can detect energy expenditure is still unsatisfactory. Additional
methods such as measurement of changes in body core temperature or spontaneous
locomotor activity can be employed to obtain a more complete collection
of data on ghrelin’s effects on energy balance in rodents. Interestingly,
ghrelin seems to decrease body core temperature by more than 1 C, an effect
possibly reflecting a ghrelin induced impairment of thermogenesis. This effect
becomes more pronounced in rodents exposed to 4 C (climate chambers). At
these challenging conditions body core temperature decreases by 2–3 C following
ghrelin administration, while saline injected controls are able to maintain
their body core temperature (as measured by intraperitoneally implanted
transponders). Either a two-dimensional infrared light beam system or the
same implantable transponders used for temperature measurement can be used
to detect changes in spontaneous locomotor acitivity following ghrelin administration
– yet another parameter, which influences the net outcome of energy
balance and eventually the amount of fat mass accumulated over time. Ghrelin
decreases locomotor activity but these effects can only be observed following
intracerebroventricular (i.c.v.) ghrelin administration, while peripheral ghrelin
injections do not seem to significantly change spontaneous locomotor activity.
Last but not least, not all calories ingested are absorbed and used. Therefore,
a simultaneous analysis of the metabolic efficiency of the rodent model under
the investigated conditions and influences is mandatory. For these purposes
metabolic cages are used to separately collect feces and urine while measuring
food intake and body weight. Later, caloric content of feces and urine are measured
in a bomb calorimeter to detect changes in metabolic efficiency or
intestinal absorption following the administration of a drug or the deletion or
overexpression of a gene in rodent models. For these purposes of accurately
measuring energy balance in rodent models, it is also advantageous to precisely
compose rodent chow with a distinct percentage of fat, protein and
carbohydrates and to then provide equally shaped pellets, which can be
used to compare different diets. While (at least in rodents) stomach-derived
ghrelin might not represent the ‘hunger-’hormone, the above described observations
indicate that ghrelin triggers a positive energy balance via a combination
of effects on physiological mechanisms, eventually increasing fat mass.
Hormonal and neuronal messages from the periphery communicate the
environmentally induced necessity for regulatory changes in order to maintain
energy balance to distinct areas of the brain, where not only sensations such as
hunger and satiety are created, but also outgoing impulses for food seeking
behavior, changes in locomotor activity or appropriate modulations of peripheral
metabolic drive are triggered. Localization and precise action of these brain
centers, as well as the precise mapping of their interactive signal transduction
pathways, remain largely unknown despite great scientific progress in this area
during the last decade. A fine tuned balance of action potentials, synaptic
neurotransmitters, feedback loops and neuropeptide expression levels between
regulatory centers in the brainstem, hypothalamic nuclei, basal ganglia, accumbens
nucleus and even the cortex underlies the constant adjustment processes
described above. The redundant multiplicity of molecular factors and physiological
mechanisms governing energy balance, which were generated due to the
evolutionary necessity to ensure sufficient caloric intake, is regarded as one
reason for the ongoing scientific failure to generate an effective pharmacotherapy
against obesity. However, these obstacles may be overcome through the
application of post-genomic research, and the understanding that we now lack
will emerge progressively. To identify and successfully modulate the essential
pathways within the complex neuroendocrine control of energy homeostasis
(fig. 1, 2), integrated efforts of research groups with complementary expertise
will become necessary. Combining neuroscience with neuroendocrine, systems
physiology, biochemistry, genetics, and cell biology approaches with clinical
studies approaches may generate sufficient knowledge to generate a pharmacological
approach for the effective and safe regulation of appetite, energy expenditure
and body composition.
environmentally induced necessity for regulatory changes in order to maintain
energy balance to distinct areas of the brain, where not only sensations such as
hunger and satiety are created, but also outgoing impulses for food seeking
behavior, changes in locomotor activity or appropriate modulations of peripheral
metabolic drive are triggered. Localization and precise action of these brain
centers, as well as the precise mapping of their interactive signal transduction
pathways, remain largely unknown despite great scientific progress in this area
during the last decade. A fine tuned balance of action potentials, synaptic
neurotransmitters, feedback loops and neuropeptide expression levels between
regulatory centers in the brainstem, hypothalamic nuclei, basal ganglia, accumbens
nucleus and even the cortex underlies the constant adjustment processes
described above. The redundant multiplicity of molecular factors and physiological
mechanisms governing energy balance, which were generated due to the
evolutionary necessity to ensure sufficient caloric intake, is regarded as one
reason for the ongoing scientific failure to generate an effective pharmacotherapy
against obesity. However, these obstacles may be overcome through the
application of post-genomic research, and the understanding that we now lack
will emerge progressively. To identify and successfully modulate the essential
pathways within the complex neuroendocrine control of energy homeostasis
(fig. 1, 2), integrated efforts of research groups with complementary expertise
will become necessary. Combining neuroscience with neuroendocrine, systems
physiology, biochemistry, genetics, and cell biology approaches with clinical
studies approaches may generate sufficient knowledge to generate a pharmacological
approach for the effective and safe regulation of appetite, energy expenditure
and body composition.
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