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5/24/2017
ERC-Zahedi
1
ENERGY BALANCE
S. Zahedi
Endocrine Research Center
Research Institute for Endocrine Sciences
Shaheed Beheshti University of Medical Sciences
2nd obesity Congress
29-30- Oct. 2009
Tehran-Iran
One of the myths of the modern world is that health is
largely determined by individual choice.
Barry R. Bloom (2000)
Each individual has his or her predetermined
energy ration= if some body uses slowly, lasts
longer
Genes
Susceptibility genes
(many genes, each with
small effect)
Monogenic syndromes
OBESITY
ENERGY BALANCE
Physical activity
Food intake
Environment/Lifestyle
Energy Balance
Basal metabolism: energy expenditure of a subject relaxed and at rest, at thermoneutrality,
8–12 hours after last food ingestion.
Adaptive thermogenesis: energy dissipated as heat in response to environmental changes.
Nervous
Control systems in the body
Hormonal
Feeding Experiments
• Forced feeding
• Measure size of food
• Introduce food for some time more than what the animal consumes ( force
feeding)
• Will lead to weight gain
• If you remove force feeding, will lead to reduced food consumption for some time
• Will return to previous value
• Restricted food ration
• Measure size of food
• Introduce restricted food size for some time (less than what the animal
consume
• Will lead to weight loss
• If you remove restricted feeding, will lead to increased food
consumption for some time
• With return to previous value
Brain Lesioning Studies
Profound obesity from destruction of
hypothalamic:
1. Paraventricular nucleus (PVN)
2. Ventromedial nucleus (VMN)
3. Dorsomedial nucleus (DMN)
Anorexia/weight loss from destruction of:
4. Lateral hypothalamic area (LHA)
Brain Centers in Energy Homeostasis
NPY
AgRP
ARC: arcuate nucleus, PVN: paraventricular nucleus,
PFA: perfornical area, FX: fornix, LHA: lateral
hypothalamic area, VMN: ventromedial nucleus,
DMN: dorsomedial nucleus, AM: amygdala, CC:
corpus callosum, OC: optic chiasm, SE: septum, TH:
thalamus, 3V: third ventricle
Phases of food in GI tract
• Cephalic Phase
– CNS is involved
– Vagus nerve
• Gastric Phase
– Presence of the food in the stomach ( Involvement of ENS
– Vagus nerve is involved ( Vago-Vagal Reflex)
• Enteric Phase
– ENS is involved
– Vagus nerves is involved
– GI Hormones
Food intake control stages
• Very short term
• Short term
• Long term
Food intake control stages
 Very short term
 Sham satiety
 Pure nervous
 Ends food consumption during each meal
 Eosophagus
 Mechanoreceptors
 Counts the bolus
 Convey the signals to CNS
 Stomach
 Mechanoreceptors
 Counts the bolus
 Stimulated by stretch
 Convey the signals via vagus nerve
 Vagotomy remove this signal
 Short term
 Through satiety
 Glucose ( Glucostatic)
 AA ( aminostatic)
 Temp.( thermostatic)
 Plasma osmolarity ( Osmostatic)
 GI hormones
 Long term
 Contents of Adipose Tissue
 Signals from fat cells to CNS
 Controls energy content of the body (body weight)
SET POINT HYPOTHESIS
Blood-borne factor(s) mediate(s) control of body weight at a
defined level (the "set point") by interacting with the hypothalamus
Factors regulate:
food intake (appetite)
energy expenditure (level of activity and body temperature)
Several discrete genetic loci and their protein products identified
Efficiency or defect in one of these may disrupt normal weight
control leading to dramatic weight gain and associated syndromes
(e.g., NIDDM)
80% of NIDDM cases are associated with obesity
Model of food intake: lipostat (adipostat) concept = signals
proportional to the size of fat stores integrate with other regulators of
food intake
Depletion of energy stored in adipose tissue increases food
consumption => larger meal sizes
Food intake is regulated within a lipostatic system for energy
homeostasis
Hypothalamus
arcuate nucleus
Appetite is
suppressed
JAK-STAT3
CNS
Leptin
receptor
MSH
from POMC neurons
Periphery
Metabolic activity
increases to burn fat
Leptin
+
Adipose
Adipose stores
are HIGH
Hypothalamus
Appetite is
enhanced
CNS
JAK-STAT3
Leptin
receptor
 AGRP from hunger neurons
Block MSH binding
 MSH
Periphery
 Metabolic activity
decreases limiting fat
burning
 Leptin
+
Adipose
Adipose stores
are low
Primary Neurons
Control of Feeding Behavior and
Satiety
Figure 24.23
Conclusion
• Physiological control of food intake and energy
intake are very efficient, If we leave the m
alone, they will work perfectly.
• Any deviation in their activity whatever is the
reason will obviously change the balance in
away that we do not want
• Some of these deviations may have
pathological nature, but some of them are
because of our behavior, it is better to leave
them to themselves.!!!!!!!!!!!!!!!
Ghasemi
24
Inputs
Table I: Neural control of appetite
Factor
CNS Effect
Peripheral Effect
-MSH (melanocortin)
satiety
Increase energy
expenditure
Cocaine-and amphetamine- satiety
regulated transcript
(CART)
-------
Serotonin
satiety
(and other effects)
-------
CCK-PZ
satiety
gallbladder contraction/
pancreatic enzyme
secretion
GLP-I
satiety
stimulates insulin
secretion
agouti-related peptide
(AGRP)
hunger
-------
neuropeptide Y (NP-Y)
hunger
-------
galanin
hunger
(for fatty food)
-------
orexins A and B
hunger
-------
Profusion of Peripheral Signals
DVC: Dorsal Vagal Complex
Dominant Inputs to Primary Neurons
Inputs
Signals Produced by Primary Neurons
Hormone
Agrp
(Agou ti)
Made By:
Arc N
(Melano cytes)
Npy
Arc N and other
areas of brain
-MSH
Arc N, NTS &
pituit ary
Cart
Arc N
Talks To:
 Mc3/4r @ LH and PVN
(mc1r)
Signal
Empty!
Notes
Mc4r most common monogen ic human obe sit y (4%);
Ay mou se mod el
Empty!
 Mc3/4r @ LH and PVN
Full !
Product of Pomc w/ ACTH and -endorph in; autocrine
nega tive feedback via Mc3r
Full !
Cocaine and amphe tamine regulated transcript (mis nomer)
Outputs to Body and Higher Brain
Hormone
Mch
Made By:
LH
Talks To:
Hypoc retin LH
Orexin 1 /2
Signal
Empty!
“fuel-guage ->fuel-pump”
Notes
Empty!
Hormone and receptor knockou ts produce narcolepsy
Trh
PVN
Pituit.(Tsh)->Thyroid(Thr) Full !
“fuel-guage ->ga s-pedal”; Mc4r ant. & MSG block lep.Trh
Dopamine
SNPC/VTA
motor/reward
D1-D4 @cauda te-putamen/
nuc leus accumbens
Empty!
Parkinson wasting; “know hung ry bu t don’ t care”;  C-P
dopamine production fixes feeding bu t no t locomotion ;
behav iors of motivation/reward/pleasure; no hyp. projection s
Chrm3 muscarinic receptor
Empty!
Chrm3 respond to Mch but no t Agrp (potentiation)
AcCholine
Endocrine Efferent Outputs
Dopamine and Outputs to Striatum
(motor activity)
(motivation/reward)
SNPC: substantia nigra pars compacta
VTA: ventral tegmental area
Opioids and amphetamines remove a GABAnergic block on dopamine production.
These drugs suppress appetite, and were initially used to treat obesity. In humans, BMI
is anti-correlated with #D2 receptors in the striatum.
Bias Toward Weight Gain
1.
Arc destruction causes weight gain.
2.
Response to weight loss bidirectional; weight gain unidirectional.
3.
Mc4r=> weight gain whereas npy=>no weight loss.
4.
AgRP/Npy neurons are more sensitive to adiposity signals than
Pomc/Cart neurons.
HOWEVER:
5.
Anabolic pathways are required for intact responses to negative
energy balance (IDDM causes negative energy balance in Npy-/mice).
6.
Anabolic pathways are required for response to decreased leptin
(Npy-/- over ob/ob mice show reduced hyperphagia).
Currently Approved Therapies
1.
Orlistat (interferes with fatty acid hydrolysis); => moderate clinical effects; side
effects include gas/diaharrea.
2.
Sibutramine (central norepinephrine/serotonin RI); => moderate clinical effects;
side effects include tachycardia and hypertension.
3.
Roux-en-Y gastric bypass (absorption and hormonal).
4.
Rimonabant (Acomplia; CR1 endocannabinoid antagonsist).
Adipokines
•
•
•
•
Adipokine is a term applied to biologically active substances found in the adipocytes
of white fat (adipose) tissue.
Adipokines may be synthesized at other sites and participate in functions unrelated
to those within adipose tissue.
Many exert proinflammatory effects and may be causally involved in obesity and
diabetes.
These adipokines include
–
leptin,
–
tumor necrosis factor alpha (TNFα),
–
–
–
–
–
interleukin (IL)-6,
plasminogen activator inhibitor-1 (PAI-1),
angiotensinogen,
and resistin.
A few others, particularly
• adiponectin and transforming growth
• factor beta-1 (TGF-β1), are anti-inflammatory and may exert protective
functions against metabolic disturbance.
Leptin receptors in the CNS
• High levels of leptin receptor mRNA and
protein are expressed in both rodent and
human
• In Hypothalamus:
– (ventromedial hypothalamus,
– arcuate nucleus
– and dorsomedial hypothalamus) that are involved
in regulating energy homeostasis are highly
enriched with leptin receptors.
Leptin receptors in the CNS
• Leptin receptor mRNA and immunoreactivity
are also highly expressed in many extrahypothalamic brain regions including:
– hippocampus,
– brain stem,
– cerebellum,
– amygdala and
– substantia nigra
Leptin In CNS
• Leptin is thought to enter the brain via two
distinct mechanisms.
– A saturable transport system is thought to enable
leptin to cross the blood brain barrier via
receptor-mediated transcytosis
– Short leptin receptor isoforms, which are capable
of binding and internalizing leptin, have been
detected on brain microvessels
• In addition,
• It appears that leptin is made and released
locally in the CNS.
– mRNA and immunoreactivity are widely expressed
throughout the brain
– So is it a neurotransmitter???
(Morash et al, 1999;Ur et al, 2002).
What is a neurotransmitter???
•
•
•
•
Can be synthesized in the nervous system
Released in the synaptic cleft
Act through post synaptic membrane
Modify postsynaptic membrane potential
Previous studies have demonstrated that leptin
inhibits:
 Peripheral insulin-secreting cells
Glucose-responsive hypothalamic neurons and
Nucleus tractus solitarius neurons
 Via activation of ATP-sensitive potassium (KATP) channels.
Similarly leptin inhibits rat hippocampal neurons by
 Increasing a K+ conductance
 It seems Ca2+-activated K+ channels are involved.
Leptin alter synaptic function
• Leptin alter the strength of excitatory synaptic
transmission under conditions of enhanced
Excitability .
– In certain conditions leptin cause hippocampal
long-term depression (LTD)
– In contrasts leptin under physiological conditions
(1 mM Mg2+), it promotes the induction of
hippocampal long term potentiation (LTP).
Leptin, learning and memory

Recent studies have implicated leptin in associative
learning and memory :
leptin-insensitive (db/db mice and fa/fa rats) rodents display
impairments in hippocampal long-term potentiation (LTP) and
long-term depression (LTD), as well as deficits in spatial memory
tasks .
Direct administration of leptin into the hippocampus enhances LTP
in vivo.
At the cellular level, leptin converts hippocampal short lasting
potentiation (STP) into LTP
Leptin also contributes to synaptic plasticity changes in the
hypothalamus as the efficacy of inhibitory and excitatory synaptic
transmission is altered in leptin-deficient ob/ob mice
Leptin and Morphological changes
• Leptin increases the number of dendritic filopodia in hippocampal
neurons
• Leptin induces actin re-organisation in hippocampal neurons
• Leptin enhances actin-based motility of filopodial extensions
• Leptin promotes formation of functional hippocampal synapses
Blood Brain Barrier
 Large interface (100-150 Cm2/kg) between circulation
and the brain
 Monolayer of endothelial cells
Few fenestrations
Few Pinocytic vesicles
Few transendothelial channels
Are joined by tight junctions
Continuous basement membrane
Astrocytic endfeet
Pericytes
Controls penetration of AA, Peptides, proteins,…
Blood-brain barrier (BBB)
 The BBB constitutes a large interface between the circulation and
the central nervous system (CNS), consisting of:
 brain and
 spinal cord.
 Its primary component is a monolayer of endothelialcells forming
the outer wall of capillaries and venules.
 These microvascular endothelial cells have few fenestrations,
pinocytic vesicles, or transendothelial channels, and are joined by
tight junctions.
 A continuous basement membrane, astrocytic endfeet, and
pericytes reinforce barrier function from the basolateral side facing
the extracellular matrix.
 The surface area of the BBB is 100 to 150 cm2/g,.
 This immense neurovascular interface controls the penetration of
amino acids, peptides, polypeptides, and proteins as well as many
other molecules .
Adipokines interact with the BBB
The hypothalamus has an intact BBB .
The interactions of adipokines with the BBB can
fall into three categories:
changing endothelial function and signaling;
Modulating signals from other adipokine and
cytokines;
 and permeation across the BBB by themselves.
The rich information from leptin provides insights
into transcellular transport across the BBB
Physiological regulation of leptin
transport
Transport of leptin into brain is reduced by fasting
and by genetic mutation and dysfunction of the
transporting receptor ObRa .
 It is increased by pretreatment with glucose .
The saturable transport system for leptin has
been demonstrated both in vivo and in vitro
and shows a diurnal rhythm .
It is partially saturated in mice with normal
weight being even more so in obese mice .
Leptin receptors ObRa-ObRd
 The short isoform of the leptin receptor, ObRa, plays a
major role in mediating leptin transport across the
BBB.
 ObRa has a high level of expression in microvessels and
high efficacy in mediating endocytosis in cell systems.
 The long isoform, ObRb, contains cytoplasmic domains
that interact with the Stats and plays a major role in
JAK/Stat signaling.
 Nevertheless, ObRa, ObRb, ObRc, and ObRd receptor
subtypes can all mediate the binding and endocytosis
of leptin in HEK293 cells .
ObRe
• ObRe is the soluble leptin receptor circulating
in blood.
• It binds leptin and interferes with ObRbmediated signaling.
• Recent evidence in vitro and in vivo shows
that this soluble receptor for leptin serves as
an antagonist not only in the signaling but also
in the transport of leptin across endothelial
cells .
Profusion of Peripheral Signals
DVC: Dorsal Vagal Complex
Role of leptin in thermogenesis
Physiological effects of Leptin
Regulation of food intake ,energy
expenditure and body weight .
Thermogenesis .
Reproductive function .
Supresses bone formation .
Directly act on the cells of liver and muscles
Related to inflammatory response .
Contribute to early hemopoiesis.
Role of leptin in reproduction
Fertility influenced by stored body fat
Leptin signals the onset of puberty .
Regulates hypothalamic- pituitary – ovarian
function .