Physiology of Body

Weight Control
Mila Citrawati
Department of Physiology
FK UPN Veteran Jakarta
2018
Concept of Energy Homeostasis

Fat is the primary form of energy storage in the human

body.
According to the first law of thermodynamics, the
amount of energy stored is equal to the difference
between energy intake and energy expenditure.
Under normal conditions, homeostatic mechanisms
maintain the difference between energy intake and
energy expenditure close to ZERO.
Body weight is determined by energy intake on one
hand and energy expenditure on the other. Imbalance
between energy intake and expenditure results in a
change in body weight.
In order to keep a perfect balance between energy
intake and expenditure, homeostatic mechanisms rely
on neural signals that emanate from adipose tissue
and from endocrine, neurological, and GI systems and
are integrated by the CNS
Role of the Central Nervous System
Two populations of neurons are responsible for the
regulation of food intake in the arcuate nucleus, one
expressing neuropeptide Y (NPY) and agoutirelated
peptide (AgRP), which when activated leads to an
orexigenic response and reduced energy expenditure,
and the other containing pro-opiomelanocortin
(POMC) and cocaine- and amphetamineregulated
transcript (CART), in which increased activity results
in an increase in energy expenditure and a decrease in
food intake
NPY is one part of the pancreatic polypeptide family,
which includes two other hormones: pancreatic
polypeptide (PP) and peptide YY (PYY).
NPY is present in large quantities in the hypothalamus
and is one of the most potent orexigenic factors
Among NPY receptors, the Y5 receptors have been
implicated as important mediators of the feeding
effect and the Y5 receptors antagonists have been
involved in recent weight-loss studies
Role of Adipose Tissue
Insulin and leptin are adiposity signals that play an
important role in the physiology of weight regulation.
Insulin may also act outside the hypothalamus in the
ventral tegmental area to suppress some aspects of
feeding
The action of leptin in the CNS results in a decrease in
food intake and an increase in energy expenditure
through the inhibition of NPY/AgRP neurons and
activation of POMC neurons
Role of the GI Tract
Gastric distension has been shown in multiple studies to
serve as a signal for satiety.
Ghrelin is a peptide predominantly produced by the
stomach.
Its secretion is increased by fasting and in response to
weight loss and is decreased by food intake.
Ghrelin is the only known circulating appetite stimulant.
It stimulates appetite by acting on arcuate nucleus
NPY/AgRP neurons and may also inhibit POMC neurons
It has been shown to play a role in stress-induced food
reward behavior by acting on the ventral tegmental area of
the brain
Cholecystokinin (CCK) is the prototypical satiety
hormone, produced by cells in the duodenum and
jejunum. It is produced in response to the presence of
nutrients within the gut lumen, specifically fat and
protein.
The satiating effect of CCK is mediated through
paracrine interaction with sensory fibers of the vagus
nerve.
Peptide Tyrosine Tyrosine (PYY) is secreted by
enteroendocrine L-cells, mainly in the distal portion of
the GI tract. It is released following meals (acting as a
meal terminator) and is suppressed by fasting
Increased levels of PYY are thought to play a role in the
early weight loss observed after gastric bypass surgery.
Pancreatic Polypeptide (PP) is secreted in response to a
meal, in proportion to the caloric load, and has been
shown to reduce appetite and food intake. It is mainly
produced in the endocrine pancreas, but also in the
exocrine pancreas, colon, and rectum.
Glucagon-like Peptide 1 (GLP-1) and Oxyntomodulin
derive from the post-translational processing of
proglucagon, which is expressed in the gut, pancreas,
and brain
GLP-1 is secreted by enteroendocrine L-cells in the
distal small bowel in response to direct nutrient
stimulation in the distal small intestine
The actions of GLP-1 include inhibition of gastric
emptying, stimulation of insulin release, inhibition of
glucagon release, and inhibition of appetite
Oxyntomodulin is also secreted in the distal small
intestine. It binds to the GLP-1 receptor, but with a
lower affinity.
It has been shown to decrease energy intake and,
moreover, increase energy expenditure
How Is Food Intake Regulated?
Hunger and satiation are controlled by hormones
that are produced in the brain and gastrointestinal
tract

Appetite is the desire to eat food whether or not there

is physical hunger; may be triggered by factors such as
time of day, social occasions, emotions, or the sight or
smell of food
Two regions within the
hypothalamus
of the brain control
hunger
and satiety
Ventromedial nucleus
Lateral hypothalamus
After a meal, satiety is triggered in the ventromedial
nucleus
Stretch receptors in the stomach signal fullness
Cholecystokinin and peptide YY send feedback to the
hypothalamus to increase satiety and decrease hunger
Nutrient absorption triggers insulin release which also
decreases hunger
Leptin, produced by adipose tissue, both suppresses
hunger and promotes energy expenditure
The lateral hypothalamus controls hunger
Ghrelin, produced by the stomach, stimulates hunger
during fasting or on a low-kilocalorie diet
Neuropeptide Y is produced in the hypothalamus and
activated by ghrelin; it stimulates hunger and LPL (lipo
protein lipase) activity
In addition to hormones, certain macronutrients,
especially protein, promote satiety and reduce food
intake
Quick Review
Food intake is controlled by hunger, satiety, and
appetite
Within the brain, the ventromedial nucleus controls
satiety and the lateral hypothalamus controls hunger
Neuropeptides, hormones, and neural signals from
the gastrointestinal tract and adipocytes communicate
hunger and satiety to the hypothalamus
Leptin and ghrelin play key roles in triggering hunger
and satiety, with ghrelin triggering hunger and leptin
triggering satiation
Evolution and an Organism’s Ability
to Maintain Body Weight
Metabolic efficiency varies among different species of
organisms and among different individuals within a species.
An individual with high metabolic efficiency will expend
less energy to perform a specific task, such as climbing a set
of stairs, than an individual with low metabolic efficiency.
Compared with an individual with low metabolic efficiency,
an individual with high metabolic efficiency is better able to
preserve body weight during negative daily energy balance
(expenditure exceeding intake), but likely to gain more
weight during positive energy balance (intake exceeding
expenditure).
Genetic Contribution to Metabolic
Efficiency and Regulation of Body Weight
Lifestyle (sedentary or active) has a clear influence on
body weight.
In rare cases, obesity has been traced to mutations in
single genes. Usually, these genes code for proteins
involved in the regulation of satiety and food intake,
such as leptin (Ob), the leptin receptor (Ob-R),
proopiomelanocortin (POMC), and the melanocortin
4 receptor (MC4R).
In one study, a group of overweight women (average
BMI ~ 29 kg/m2) were kept on a low-calorie diet for a
period of time until their BMI decreased to < 25
kg/m2, the defined upper range of what is considered
normal weight. When these age-, weight-, and BMI-
matched women were separated based on ethnicity (in
this case African-American or white), differences in
resting energy expenditure were apparent before and
after weight loss. Different ethnicities also have
different resting energy expenditures
Control of Body Weight at the
Molecular Level
Body weight regulation and energy homeostasis is
controlled by a myriad of metabolic pathway
intermediates and endocrine control systems.
Food intake is under the control of the central nervous
system through many interconnected neuroendocrine
and neurotransmitter circuits
Energy expenditure is regulated by the autonomic
nervous system and numerous endocrine hormones,
the most prominent of which are the thyroid hormone
system
In vertebrates, insulin regulates energy homeostasis
and body weight through both the central nervous
system and through its effects on lipid and glucose
metabolism
In healthy individuals, insulin levels rise after a meal.
Insulin readily crosses the blood-brain barrier to enter
the central nervous system and bind to receptors
located in the hypothalamus, the area of the brain that
controls feeding behavior and energy homeostasis.
Insulin is known to inhibit food intake by decreasing
the expression of the orexigenic neurotransmitter
neuropeptide Y
Molecular Mediators of Feeding Behavior and
Energy Expenditure
Neuropeptide Y (NPY), a potent endogenous central
appetite stimulant, is synthesized by cell bodies in the
arcuate nucleus of the hypothalamus and transported
axonally to the paraventricular nucleus (PVN), where
the highest concentrations are found
NPY also is synthesized and released from the adrenal
gland and sympathetic nerves, but peripherally
synthesized NPY does not pass the blood–brain
barrier.
The mixed α- and β-adrenergic agonists epinephrine and
norepinephrine may act as both appetite stimulants (α-
adrenergic) and suppressants (β-adrenergic).
Dopamine and serotonin act as appetite suppressants
The catecholaminergic and serotoninergic systems are
exploited by current antiobesity medications, which act to
decrease energy intake via the sympathetic nervous
system (eg, phentermine), to decrease appetite by
inhibiting serotonin reuptake (eg, d-fenfluramine), or by
affecting both catecholaminergic and serotoninergic
systems (eg, sibutramine).
Endogenous Chemicals Affecting Energy
Intake and Expenditure: Appetite Stimulants
NPY (site of action PVN) :
* effect on energy intake  the most potent
endogenous stimulant of food intake identified;
increased during food restriction
* effect on energy expenditure  increased of
lipoprotein lipase activity-sympathetic nervous
system tone-thermogenesis after central
administration

*Note : PVN = paraventrikular nuclei

Norepinephrine and epinephrine (site of
action PVN)
* effect on energy intake  α-adrenergic
stimulation, stimulates food intake
* effect on energy expenditure  decreased
lipolysis - heart rate (attributable to
vasoconstriction) - energy expenditure
Insulin (site of action VMH, LH, liver, fat, muscle)
*effect on energy intake  central administration :
decreased NPY and increased food intake
*effect on energy expenditure  increased
acylglyceride synthesis, decreased lipolysis,
decreased NPY decreased lipoprotein lipase
activity, sympathetic tone and thermogenesis

*Note : VMH = ventromedial hypothalamus

LH = lateral hypothalamus
Glucocorticoids
* effect on energy intake  increased food intake; increased
expression of NPY mRNA and [NPY]; adrenalectomy
decreases fat mass in rodents with genetic and surgical
(VMH-lesioned) obesities; increased brain levels of
norepinephrine and food intake stimulating effects of
central
* effect on energy expenditure  decreased thermogenesis,
perhaps attributable to decreased CRF synthesis

*Note : CRF = corticotropin releasing factor

Galanin (site of action PVN)
*effect on energy intake  increased food intake
and increased preference for fat intake, may depend
on norepinephrine because central galanin
administration  increase norepinephrine, and
galanin effect is blocked by α1-adrenergic
antagonists
*effect on energy expenditure  decreased
circulating concentrations of insulin and
corticosterone
Opioids (dynorphins, endorphins, and
enkephalin)
*effect on energy intake  increased food
intake after activation of μ or δ receptor is
blocked by opiate antagonists
Growth hormone releasing hormone
*effect on energy intake  increased of appetite
Somatostatin
*effect on energy intake  increased food intake
Polypeptide YY
* effect on energy intake  increased food intake
MCH
*effect on energy intake  MCH mRNA is over
expressed in the hypothalamus of Lep-ob mice;
increased during fasting in normal and obese animals;
increased food intake when injected centrally in mice
Neurotensin
*effect on energy intake  increased food intake

*notes : MCH = melanin concentrating hormone

ob = ob protein = leptin
Endogenous Chemicals Affecting Energy Intake
and Expenditure: Appetite Suppressants
Norepinephrine and epinephrine (site of action LH (β-
effect))
*effect on energy intake : β-adrenergic stimulation is
anorectic
*effect on energy expenditure : β-adrenergic
stimulation increased sympathetic nervous system
activity, increased [thyroid hormone], increased
energy expenditure; increased lipolysis
Dopamin (site of action LH), effect on energy intake 
anorectic
Serotonin (site of action VMH), effect on energy intake 
anorectic
Leptin (site of action VMH arcuate nucleus)
*effect on energy intake  decreased food intake in Lep-ob
mouse
*effect on energy expenditure  decrease NPY mRNA,
increased thermogenesis and sympathetic nervous system
activity (not solely attributable to effects on NPY because
NPY-knockout mice still respond to leptin)
Cholecystokinin (CCK) (site of action vagus nerve,
which projects to the PVN (type A receptor) and brain
(type B receptor))
*effect on energy intake  anorectic effect of
peripherally administered CCK is blocked by
abdominal vagotomy; centrally administered CCK also
has anorectic effect, perhaps by interaction with
adrenergic receptors
Corticotropin releasing factor (CRF) (site of action
PVN)
*effect on energy intake  anorectic (?), perhaps by
effects on corticotropin or glucocorticoid production ;
decreased [CRF] in hypothalamus of Lep-fa rats
*effect on energy expenditure  increased
sympathetic nervous system output; increased
thermogenesis; increased energy expenditure
Urocortin (site of action PVN)
*effect of energy intake  anorectic, perhaps via
mechanisms similar to CRF
Glucagon (site of action vagus nerve, which projects to
the PVN)
*effect on energy intake  anorectic effect of
peripherally administered glucagon is blocked by
abdominal vagotomy
*effect on energy expenditure  May decrease energy
expenditure because humans given glucagon
intramuscularly gain weight despite decreasing caloric
intake
Glucagon-like peptide-1 (GLP-1) (site of action
hypothalamus)
*effect on energy intake  anorectic, may transduce
the anorectic signal from leptin; central
administration of GLP-1 antagonist  increased
feeding in response to NPY
g-Aminobutyric acid (site of action VMH) effect on
energy intake  anorectic
Glucose (site of action VMH, LH, liver, fat, muscle)
effect on energy intake  anorectic
Refference
Louis Chaptini and Steven Peikin, Physiology of
Weight Regulation, 2016
Betsy B. Dokken, PhD, NP, CDE, Tsu-Shuen Tsao,
PhD, The Physiology of Body Weight Regulation: Are
We Too Efficient for Our Own Good?, 2007
Michael Rosenbaum, MD, and Rudolph L. Leibel, MD,
The Physiology of Body Weight Regulation: Relevance
to the Etiology of Obesity in Children, 2018
Stephen J McPhee, Gary D Hammer, Pathophysiology
of Desease, 2010