Food and Energy Regulation

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• Food and Energy Regulation
• January 12th, 2005
• PSY 398

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Outline

• Brief Review of Body Weight Regulation
• Peripheral Factors
• Social/Environmental
• Glucose Levels
• CCK
• Central Factors
• Neuroanatomy Neurochemistry
• LH Glutamatergic NMDA System ? HUNGER
• VMH Leptin ? SATIETY
• Food Seeking Motivation NAcc

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Body Weight Regulation

• Animals regulate their body weight within very
  narrow limits over the LONG TERM
• Energy intake (food) energy expenditure
  (activity and heat loss)
• Over one day? gain weight in day, lose at night
• BUT, from month to month, weight is STABLE!!

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Body Weight Regulation Input

• Enriching caloric value of food causes animals to
  eat less
• Diluting caloric value of food causes animals to
  eat more
• If food is only made available once a day, an
  animal will quickly learn to increase its
  caloric intake at that meal
• In humans, if we eat a big meal, our next meal is
  likely to be smaller

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Body Weight Regulation Output

• If an animal is put into a reduced temperature,
  they will increase thermoregulatory behaviour and
  physiology and increase food intake
• Lactating animals increase their food intake
• Animals forced to run in a running wheel will
  increase their food intake when released

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Body Weight Regulation Set Point

• As we said, animals regulate their weight very
  well
• After being food deprived, and then allowed to
  eat ad lib, animals will overeat until they reach
  their
• set point
• Same goes when an animal is forced fed they will
  under-eat when allowed to eat freely (until they
  reach their set-point)

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Why is it SO hard to loose weight?

• If fat is surgically removed, body metabolism
  changes and the fat is redistributed
• Dieting also causes changes in metabolism
• Our bodies fight HARD to maintain set-point!!!

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Factors Affecting Food Intake

• Meal Schedules
• Tendency to eat at the same times each day
• Environmental Cues
• Classical (Pavlovian) conditioning
• Social Factors
• Females eat less in the presence of males female
  dieters with females eat less males of large
  families eat more than those is smaller families
• Taste
• Sweet taste before meal increases intake
• More flavors in meal increases intake
• Physiological Mechanisms

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• Today, we are going to examine SOME of the
  physiological mechanisms responsible for body
  weight regulation
• There are both short-term (peripheral) and
  long-term (central, adipose stores, leptin etc.)
  mechanisms mediating weight regulation

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The liver and brain respond to two types of
signals short-term and long-term

• Short Term Receptors in the liver and brain
  detect the short-term signals, which are
  determined by the availability of nutrients
  (primarily glucose) in the blood
• Long Term Receptors also detect long-term
  signals provided by adipose tissue (fat tissue)
• A fall in blood glucose level OR a fall in fatty
  acids level causes hunger

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• Peripheral mechanisms

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Short Term Regulation

• Glucose is the most important sugar used by the
  body (simple carbohydrate)
• The body can also derive energy from fatty acids,
  but the brain is heavily dependent on glucose
• Glucose is stored as glycogen in the liver
  (reserves)
• Glycogen can be converted back into glucose when
  needed

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Short Term Regulation

• Two pancreatic hormones control the shuttling of
  glucose in and out of storage
• Insulin secreted by the beta islet cells and
  promotes the conversion of glucose to glycogen
• Glucagon secreted by the alpha islet cells and
  promotes the breakdown of glycogen to glucose

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Carbohydrates provide energy for body and brain
Insulin

• Glycogen
• (complex, insoluble carbohydrate)

Glucose (simple sugar)
Glucagon

• When we are hungry, blood glucose levels fall
• The pancreas secretes glucagon (which stimulates
  the conversion of glycogen into glucose)
• The glucose reaches the CNS, where it is absorbed
  and metabolized by the neurons and glia

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But what signals the release of insulin?

• Insulin release is stimulated by
• Presentation of Food
• During Digestive Phase
• During Absorptive Phase
• So when we eat, insulin is released so that
  glucose may be converted into glycogen (for
  storage)

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Insulin The Evidence

• Animals whose insulin levels have been lowered
  become hungry and eat large meals
• Moderate levels of insulin result in normal meals
• These two results support the idea that insulin
  levels signal satiety to the brain

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Long Term Regulation

• Long-term energy storage is accomplished by the
  depositing of fat in adipose tissue
• Fat may either be eaten or made in the body from
  glucose plus other nutrients
• Fat may be broken down either into fatty acids,
  to supply energy to most of the body, or into
  glucose, for use by the brain

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What stops a meal?

• The feedback produced by tasting, smelling and
  swallowing food provides the first satiety signal
• The stomach contains nutrient detectors that tell
  the brain how much food has been received
• Signals originating in the intestines
  (cholecystokinin CCK) may also produce satiety,
  so do the signals from the liver (sensitive to
  the glucose). These signals convey to the brain
  via the vagus nerve
• Leptin, a peptide hormone secreted by
  well-nourished adipose tissue decreases food
  intake

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Cholecystokinin (CCK)

• CCK is a peptide hormone that is secreted by the
  gut in response to food (especially when there is
  a lot of fat or protein in the food)
• CCK acts on receptors on vagus nerve to provide
  sensory information to the brain
• CCK may signal satiety for two reasons
• Levels change in parallel with the presence of
  food in the gut
• CCK can act as a neurotransmitter in the brain

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CCK in Satiety The Evidence

• Gibbs et al., (1973)
• Exogenously administered CCK inhibits food intake
  in rats (behaviorally, the rats seem satiated)
• Kissileff et al., (1981)
• High doses of CCK infusion decreased liquid meal
  intake in human volunteers

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CCK Receptors

• CCK seems to be involved in satiety signalsbut
  how does this work?
• CCK receptors are found in high concentrations in
  the vagus nerve, cerebral cortex, nucleus
  accumbens, olfactory bulb and basal ganglia
• Lower concentrations of CCK receptors have also
  been identified in the hippocampus, hypothalamus,
  lower medullary regions and spinal cord

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CCK receptors

• CCK has two types of receptors, CCKA and CCKB
• In the rat, CCKA receptors are found in the
  pancreas, on vagal afferent and enteric neurons,
  and at a number of brain sites
• CCKB receptors are distributed widely in the
  brain, are present in the afferent vagus nerve,
  and are found within the stomach
• It seems that CCKA, but not CCKB receptors play a
  important role in satiety

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..Side Note..

• Antagonist a molecule, usually a drug, that
  interferes with or prevents the action of a
  transmitter
• Agonist a molecule, usually a drug, that binds a
  receptor molecule and initiates a response like
  that of another molecule, usually a
  neurotransmitter

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The Evidence

• CCKA receptor-selective agonists caused a
  dose-dependent suppression of food intake
• But, CCKB-specific agonists failed to produce
  satiety
• CCKA antagonists blocked the satiety effects of
  exogenously administered CCK in a number of
  settings
• CCKA antagonist but not CCKB antagonist,
  increases liquid and solid food intake in the rat
  in a variety of experimental settings

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What does that MEAN??!!

• This all suggest that the CCKA but NOT the CCKB
  receptors are primarily involved in satiety
• If you enhance it in function, you decrease food
  intake
• If you decrease function, then you enhance the
  tendency to eat

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Brain Mechanisms Neurochemistry
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The Dual-Centre Theory of Eating

• The dual-center theory of eating proposed that
  two brain centers, acting in opposition, control
  the intake of food
• According to this theory
• Lateral hypothalamus (LH) HUNGER CENTRE
  (stimulates feeding behaviour)
• The ventromedial hypothalamus (VMH) SATIETY
  CENTRE (inhibits feeding behaviour)

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• VMH

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The role of LH in hunger

• The larger the size of the LH lesions, the lower
  the new target body weight will be
• Once recovery has occurred and the new target
  weight has been reached, this new weight is
  "defended"
• If an LH-lesioned animal is forced to gain weight
  it will return to the new target weight when
  allowed to feed normally
• If it is given unpalatable food, its weight will
  fall just as in a normal rat, and will rebound to
  the defended target weight when normal food is
  provided
• These data imply that LH-lesioned animals get
  hungry and will eat, so the LH cannot be the sole
  hunger center in the brain

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• Neurochemistry

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The LH Glutamate System

• Glutamate is an excitatory amino acid that
  behaves like a neurotransmitter
• Glutamate binds on three types of receptors
• NMDA receptors
• AMPA receptors
• KA receptors

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Glutamate Feeding

• Glutamate and its receptor agonists (e.g., NMDA),
  elicit intense feeding responses when
  microinjected directly into the LH
• NMDA receptor antagonists suppress feeding
• Firing rate of LH neurons increases during
  spontaneous feeding
• An increase in endogenous extracellular
  glutamate, specifically in the LH, is coupled
  with the onset of feeding behavior (see next
  slide for description)

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Subjects were food-deprived for 16 hrs. Feeding
lasted 2 min.
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Stanley et al., (1996)

• Examined the involvement of LH glutamate and its
  receptors in various aspects of natural eating
  behavior and body weight gain
• This study was specifically interested in
  glutamate and the NMDA receptor in the LH

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Stanley et al., (1996)

• Injected NMDA receptor antagonist into the LH and
  examined feeding elicited by
• injection of NMDA
• food deprivation
• the onset of the nocturnal phase of the circadian
  cycle
• (SHORT TERM EFFECTS!)
• Furthermore, they were interested in the LONG
  TERM EFFECTS of daily injections of the NMDA
  antagonist on food intake and weight gain

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• The big question
• Do NMDA receptors selectively mediate eating?

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Experiment 1 NMDA receptors and eating elicited
by NMDA, KA, or AMPA

• Purpose To determine whether LH glutamate and
  the NMDA receptors might mediate eating occurring
  by injections of MNDA, KA or AMPA
• Rats were given two unilateral LH injections
• The first injection was a dose of the selective
  NMDA antagonist or vehicle
• Followed 5-10 min later by either NMDA, KA , or
  AMPA
• Food intake measured 60 min after the second
  injection

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Experiment 1 NMDA receptors and eating elicited
by NMDA, KA, or AMPA

• Another group of 13 rats was given three tests
  consisting of two consecutive unilateral LH
  injections of
• 1) vehicle then vehicle (control)
• 2) vehicle then NMDA AMPA or KA
• 3) NMDA antagonist followed by NMDA, AMPA or KA

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LH injection of D-AP5 ( NMDA antagonist) produced
suppression of NMDA-elicited eating, but not
AMPA or KA-elicited eating
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Experiment 2 NMDA receptors on food-deprivation
elicited feeding

• Purpose To determine whether LH glutamate and
  the NMDA receptors might mediate eating occurring
  subsequent to a fast
• 9 rats were food deprived for 24 h
• Given bilateral LH injections of either vehicle
  or NMDA antagonist
• Freshly prepared food was returned, and intakes
  were
• measured

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Bilateral LH injection of D-AP5 powerfully
suppressed eating elicited by 24 h of food
deprivation
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Experiment 3 NMDA receptors and nocturnal eating

• Purpose to determine whether LH glutamate and
  NMDA receptors might mediate nocturnal eating
• Just before the onset of the dark phase 10 naive
  satiated rats were given bilateral LH injections
  with vehicle or antagonist
• Food intake was measured

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D-AP5 injected into the LH produced a significant
overall suppression of spontaneous eating
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Experiment 4 NMDA receptors and long-term
regulation of eating and body weight

• Purpose To determine whether LH glutamate and
  NMDA receptors might be involved in long-term
  regulation of eating behavior and body weight
  control
• Three groups of rats (matched for body weight and
  daily food intakes) were given the following at
  the onset and middle of the dark phase
• No treatment
• Bilateral LH injections of NMDA antagonist for 8
  days
• Bilateral LH injections of vehicle for 8 days
• Food intake and body weight were measured daily
  for 6 days before the injection period, during
  the 8-day injection period, and for 14 days
  thereafter

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Bilateral LH injections of D-AP5 markedly
suppressed daily food intake and body weight
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Summary

• LH injection of NMDA antagonist dose dependently
  suppressed eating elicited by LH injection of
  NMDA, or by food deprivation
• NMDA antagonist also suppressed nocturnal eating
  and decreased body weight
• In contrast, this NMDA receptor antagonist had no
  significant effect on eating elicited by LH
  injection of either KA or AMPA

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Summary

• These data suggest that NMDA acted to elicit
  eating via actions on LH NMDA receptors, rather
  than by possible crossover effects on other
  receptors
• Activation of subsets of LH neurons expressing
  functional NMDA receptors is sufficient to elicit
  eating

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Neuropeptide Y

• NPY is a peptide transmitter synthesized in the
  arcuate nucleus in the hypothalamus
• Released at terminals in dorsal hypothalamic
  areas including the paraventricular nucleus (PVN)
• The peptide exerts a robust stimulatory effect on
  food intake, insulin and glucocorticoid secretion
• NPY infused into the LH and PVN produces eating
  infused in the PVN also produces metabolic
  effects
• Levels of NPY are increased by food deprivation
  and lowered by eating
• Five NPY receptors are identified NPY1 plays an
  important role in feeding.

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The role of VMH in satiety

• VMH lesioned animals exhibit hyperphagia
  (ravenous eating)
• Rate of consumption is two to three times greater
  than normal
• This dynamic phase of weight gain lasts a few
  weeks
• The animal then enters into the static phase

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The role of VMH in satiety

• During the static phase, weight stabilizes and
  food intake levels off
• At this point, VMH-lesioned animals show normal
  levels of satiety after eating
• Thus, it is unlikely that the VMH is the sole
  determinant of satiety

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VMH Lesioned Rats

• If VMH-lesioned animals are
• force-fed during the static phase, they will
  decrease food intake later and return to the
  plateau weight level of the static phase
• food deprived during the static phase, they will
  return to the plateau weight when allowed to eat
  freely

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VMH Lesioned Rats

• If VMH-lesioned animals are provided only with
  normal lab "rat chow" (which must be rather
  boring!), they will not show the massive weight
  gain normally associated with VMH damage
• If their food that has been made bitter, the
  animals will lose weight
• It seems that VMH lesions may act to make animals
  overly responsive to the palatability of food

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Leptin---a satiety signal

• Leptin is a hormone secreted by well-fed adipose
  tissue
• It suppresses eating and raises the animals
  metabolic rate
• Leptin levels increase in rodents within hours
  after a meal and in humans after several days of
  overfeeding
• Decrease in both species within hours after
  initiation of fasting
• Leptin's effects on body weight are mediated
  through effects on hypothalamic centers (arcuate
  nucleus NPY system) that control feeding behavior
• Leptin also inhibits the production of NPY

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• Food Seeking and Motivation

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Motivation Food-Seeking

• Food-seeking is the flexible approach behavior
  that an animal or person emits before the
  motivational goal is found
• Food, as you know, is a primary reinforcer
  hungry animals will work very hard to gain access
  to food!
• Instrumental behaviour or operant responses
  performed to gain access to a goal are a type of
  appetitive behavior easily measured in standard
  behavioral neuroscience laboratories (as you will
  recall from your reading)

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Neural Correlates of Motivation

• The most important brain system involved in
  motivation is the mesolimbic dopamine system
  (Ventral Tegmental Area Nucleus Accumbens)
• Other systems related to the VTA-NA system
  include the glutamatergic systems, GABA systems
  and opioid systems
• These systems interact with the hypothalamic
  systems (LH, VMH, PVN)

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Dopamine

• Dopamine (DA) is found in many brain regions,
  including the Nucleus Accumbens (NAcc)
• Interference with DA transmission impairs motor
  acts that involve responsiveness to motivational
  stimuli (e.g., food)
• The nature of these behaviour deficits is unclear

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Dopamine

• Some research suggests that DA systems are
  involved in sensoimotor and motor functions
• Other research suggests that the DA systems are
  involved in reward
• Disruption of DA systems blunts rewarding impact
  of stimuli such as FOOD, water and commonly
  abused drugs

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T-Maze Review of Earlier Literature

• One arm consists of high density reinforcement
• One arm consists of low density reinforcement
• One group of rats was trained with a vertical
  barrier on the high density arm the other arm had
  no such barrier cost-benefit decision
• Another group of rats had no barriers on either
  arm
• Found that when administered DA antagonist, rats
  without the barrier were unaffected
• BUT, the vertical barrier reduced the number of
  selections from the high density arm and
  increased the selections of the low barrier arm
  (no barrier)

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• Why did this happen?
• Motor problems? (i.e., inability to climb the
  wall)
• Was the food less rewarding? (i.e., less
  motivating?)
• Could this have something to do with
  COST-BENEFIT?
• Maybe it was more adaptive to go for the lower
  reinforcement when forced to climb the wallbut
  what would happen if the choice was ALL OR
  NOTHING?!!??

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Cousins et al., (1996)

• Cousins et al., (1996) aimed to answer this
  question
• They employed the use of a T-maze cost/benefit
  procedure to study the role of DA in behavioral
  activation

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Cousins et al., (1996)

• Different groups of rats were studied under 2
  versions of the T-Maze task
• One arm contained high reinforcement density (4
  food pellets) that was blocked by a vertical
  barrier), and the other of low density
  reinforcement (2 pellets) but no barrier
• The second version of the T maze was identical to
  the first, expect this time, instead of 2 pellets
  (low density reinforcement), there were NO
  PELLETS

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Cousins et al., (1996)

• 4 groups of rats
• 2 groups with 6-OHDA lesions (destroy DA
  terminals) of NAcc (this causes dopamine
  depletion in the NAcc)
• 30 trials per day
• Rat was placed back in the start arm for the
  initiation of each trial
• Arm choice was recorded for each trial, and two
  latency measures were obtained
• 1. latency to leave the start box
• 2. latency to reach the goal

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The DA-depleted ratstested under the 4-2
condition made less HD choices and more LD choices
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The DA-depleted ratstested under the 4-2
condition made more LD choices
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DA depleted rats in the 4-0 condition climbed the
barrier for the reward!!
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The DA-depleted rats in the 4-0condition had
significantly higher latencies to leave the start
box and to reach the goal
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Summary

• There was a substantial shift in behavior from
  the HD arm to the LD arm shown by DA-depleted
  rats
• Rats with NAcc DA depletions in the 4-2 condition
  made significantly fewer HD arm selections and
  made significantly more LD arm selections
• The shift in behavior of rats in the 4-2
  condition following NAcc DA depletions does not
  seem to be due to a fundamental inability to
  climb the barrier per se (doesn't look like a
  motor thing!)
• NAcc DA may participate in the process through
  which organisms overcome response costs or cross
  energy barriers in order to obtain access to
  significant stimuli such as food

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Wrap Up

• Body weight regulation Insulin, glucagon,
  glycogen
• Dual Centre Theory (LH VMH)
• Hunger and Satiety Signals (especially CCK)
• LH Glutamate System (NMDA)
• Food Seeking and Motivation (NAcc)