Tuesday, Nov 2 VOTE VOTE VOTE VOTE

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Tuesday, Nov 2VOTEVOTEVOTEVOTE
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Lipostat - feedback control system for fat
How does the body/brain know about and control
use and long term storage of fat? - many
contributing factors- all interact- not fully
understood
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• Information about body fat levels is signaled by
• Insulin
• Leptin
• Levels are proportional to amount of body fat
• Levels decrease during fasting
• High densities of receptors are found in brain
• regions important to food intake regulation
• Meals increase the concentration of insulin in
  CSF
  and in the hypothalamus itself
• Administration of insulin reduces food intake
  and body fat.

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The Basic Lipostat - a set point theoryFat
cells secrete a hormone, leptinAmount of leptin
is proportional to amount of fat tissue.Low
leptin in blood -- triggers hypothalamus
to secrete NPY (neuropeptide Y) to increase
eating.High level in blood -- triggers
melanocyte stimulating hormone to decrease
eating.
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Some mice have a recessive condition where they
have no receptors for leptin get very
obese!Condition not known in humans, but basic
lipostat seems to work.Clinical trials with
leptin (began in 1990s)- 75 obese people were
given daily leptin injections- placebo group
lost 1.4 kg in 6 mo- high dose leptin lost 7.1
kg- dose was very high (30 mg/day)- recombinant
leptin cost 100/mgExpensive and 15 had an
allergic reaction at injection site
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Actions of NPY- increase food intake-
decreases energy expenditure- decreases
reproductive function- decreases body
temperature- increases activity in the
parasympathetic system reduces sympathetic
activityFood intake then exceeds energy
expenditure.(Insulin inhibits NPY)
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Actions of melanocyte-stimulating hormone-
decreases food intake- increases energy
expenditure- increases activity in the
sympathetic systemEnergy expenditure exceeds
food intake. (Mutations in brain receptor for
alpha-MSH associated with obesity only in 4 of
people with familial obesity)
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Other Active PlayersEndocannabinoids
stimulate appetiteSerotonin triggers signals
to/in hypothalamus related to satiety inhibit
appetiteSome diet pills elevate serotonin
levels or actions Dexfenfluramine (Redux)
removed from market in 1977 due to pulmonary
hypertension. Also can cause depression
following overuse of SE release. Other similar
drugs still on market Phentermine (Adipex)
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• Problems with Set Point Theories
• Inconsistent with evolutionary pressures such as
  an unpredictable food supply. Need a system that
  prevents deficits not one that just responds to
  deficits.
• We dont reliably stop eating when full or eat
  only when we are hungry.
• Other important factors are not considered
  tastes, social influences, pleasure of eating

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Evolutionary forces - varying food supplies make
fat storage adaptive.- eating high calorie foods
helps meet energy resource needs - we seek and
desire them. Thrifty genes - control ability
to store fat from feast to help you make it
through a famine. No famines - get
fat(Balanced against the selection pressures
from having too much fat and being less able to
avoid predators a contrasting selective
pressure)
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Settling Point TheoryLipostat may be set early
in development to establish your own range of fat
storage (defended level of body fat)High and
low leptin levels are relative to
individual.Set on basis of tuning of feedback
loops in response to genetic and environmental
interactions.
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I exist in environment X which gives me the
following energy resources and reserves. These
must be right. Set myself up to function best at
these settings. The settling points can be
reset only by radical changes in environment for
sustained period drugs used to treat obesity
change in composition of diet regular
exercise
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• OBESITY
• defined by a Body Mass Index 30
• BMI chosen because it correlates best with
  increased risks for disease and death, and with
  total body fat for most people
• BMI weight (kg)/ height (m)2
• BMI (weight (pounds)/height(inches)2 ) x 703

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Obesity cause1. Complex disease caused by
excessive calorie consumption and/or inadequate
physical activity. Interactions with genetics,
behavioral, physiologic, and environmental
factors2. If intake exceeds expenditure, excess
stored as fat. 3. A genetic predisposition -
twin and adoption studies4. Several genes are
related to being fat rare to have a genetic
disorder though less than 2 of obese.
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Obesity cause5. Not as simple as a failure to
respond to leptin, etc - in mice, yes in human,
no6. Thrifty genes are not compatible with
sedentary lifestyle and high fat foods.
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• Obesity Prevalence
• 61 of adults were overweight or obese (BMI 25)
  in 1999
• 13 of children (6-11 yrs) and 14 of adolescents
  (12-19 yrs) were overweight in 1999 (defined as
  greater than 95th percentile for BMI. Prevalence
  for adolescents has tripled in last 20 years.
• Societal costs of treatment - 7 of all
  healthcare expenditures in 2000, 117 billion

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• Obesity Health Consequences
• 300,000 deaths/yr in US are associated with
  obesity
• Associated with heart disease, type 2 diabetes,
  stroke, gall bladder disease, certain types of
  cancer, asthma, sleep apnea, arthritis,
  depression
• In women, irregular menstrual cycles and
  infertility
• Social, academic, and job discrimination

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• Obesity Health Consequences
• 5. In pg obese women
• 10 fold increase in maternal high blood pressure.
  
• Inc risk for death of mom and infant.
• Inc gestational diabetes
• Inc infant low blood sugar at birth (may cause
  brain damage and seizures)
• Inc risk for neural tube defects

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• Obesity Health Consequences
• 6. In kids
• Increased risk for heart disease and type 2
  diabetes
• Social discrimination
• Losing just 10 of your bodyweight can improve
  health!

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Rhythms, Sleep, Dreaming
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• Human Evolution
• Origins in equatorial Africa
• Days and night are about equal in length
• Differences from day to night are bigger than
  across seasons
• Our adaptations relate more to day-night
  differences
• Behaviors are governed more by daily cycles than
  seasonal ones
• Behavior dominated by a rhythm of daylight
  activity and nocturnal sleep (diurnal pattern)

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• Human Evolution
• Obtain our food and are most active in daylight
  sleep at night
• Temperature variations make it conservative of
  energy use to be out in day and sleep at night
  minimizes use/loss of energy
• Vision best in day allowing food to be found more
  easily and predators to be avoided
• Biological rhythms control our day-night cycle.
• Rhythms for activity, consciousness, body
  temperature, blood pressure, cellular activity,
  metabolic rate, etc.

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• Circadian rhythms - about a day in length
• Sleep-wake cycle
• synchronize behavior and state to changes in the
  environment
• may have evolved to conserve the bodys energy
• the controller of rhythms (internal clock) is in
  the hypothalamus
• The suprachiasmatic nucleus (SCN)

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Experiments by Aschoff and Weber in Germany

• subjects lived underground for one month
• no external cues
• free running cycle of 25 hours
• internally controlled by the hypothalamus (and
  pituitary and Reticular Activating System)

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• Internal clock is synchronized with external cues
  zeitgebers (time-givers) - Light, alarm clocks,
  eating patterns
• When out of synch disorientation (jet lag)

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• Internal clock in hypothalamus cluster of cells
  known as the suprachasmatic nucleus.
• Early studies by Richter (30s-60s) lesion
  hypothalamus, damage clock.
• More and more precise studies identified the
  specific cells.
• Pathway from the eye to suprachiasmatic nucleus
  retinohypothalamic pathway carries info about
  light.
• Other pathways pineal gland thalamus.

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• Neurons in suprachiasmatic nucleus
• Rhythmic metabolic pattern (more active in day)
• Neuronal activity greater during light period
• Dissect from surrounding cells, these neurons
  still show rhythm (so coming from within)
• Rhythm is genetically specified (shown for many
  generations precluded from influence of
  zeitgebers also transplantation studies)

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Other rhythms

• Circadian rhythms
• Ultradian rhythms period less than a day occur
  more than once a day
• a 90 minute cycle that repeats through the day
  and night
• variations in activity level and cognitive
  performance show a 90 minute rhythm
• Infradian rhythms more than a day, less than a
  year (menstrual cycle)
• Also circannual around a year seasonal
  rhythms (migration hibernation)