Monday, Mar 27 Part III of course Regulation of Internal States 1st 14 remain from last time power o

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Monday, Mar 27 Part III of courseRegulation
of Internal States1st 14 remain from last time
(power outage)
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Role of insulin 1) aids use of glucose -
movement from blood into cells 2) promotes
conversion of blood-borne useable fuels to
stored forms (glucose to glycogen and fat amino
acids to protein) 3) aids storage of glycogen in
liver and muscle fat in adipose tissue
proteins in muscle
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Nobel prize for Insulin discovery 1923 Banting
and Macleod - Canadian
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Role of Glucagon 1) stimulates conversion of
glycogen into glucose 2) promotes release of
fatty acids from storage in adipose tissue 3)
aids in conversion of fatty acids to useable
energy (ketones) for muscles
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Feedback system for control of glucose and
glycogen levelsFood in digestive tract--gt
available glucose--gt glucose in blood --gt brain
reads levelsdirectly and gets info. from the
vagus nerve from liverTells pancreas to secrete
insulin--gt tells liver to convert glucose to
glycogen
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Food in digestive tract--gt available glucose--gt
glucose in blood --gt brain reads levelsTells
pancreas to secrete insulin--gt tells liver to
convert glucose to glycogenGlucose levels in
blood fall --gt brains reads and tells pancreas to
secrete glucagonTells liver to convert glycogen
to glucose
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Glucostat - feedback control system for glucose
Brain centers that contain glucose
detectors1. Brainstem - medulla and pons -
process information from vagus nerve coming from
the liver analyze the glucose levels in the
surrounding tissue2. Hypothalamus
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Brain centers that contain glucose detectors1.
Brainstem - medulla and pons - process
information from vagus nerve coming from the
liver analyze the glucose levels in the
surrounding tissue2. Hypothalamus - several
areas contain glucose detectors and other
relevant detectors also process information from
other sources3. Circumventricular organs
(lining of ventricles)
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Information about body status is signalled by
1) stomach and gut (cholecystokinin) 2) liver -
vagus nerve 3) blood - glucose and several
hormones4) fat cells - leptin
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Diseases related to glucose regulation1.
Diabetes mellitus (type 1 diabetes) early
childhood onsetPancreas stop producing
insulin.Brain can use glucose from diet but body
cannot.Excess glucose in blood cannot be stored
goes to kidneys for removal increases thirst
to help, but dehydration may result.Excess
glucose can damage tissues like kidneys, retina,
peripheral nerves also results from decreased
blood flow acidosis.
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Diseases related to glucose regulation1. Type
2 Diabetes loss of response to insulin (insulin
resistance) as well as reduced insulin
releasemajority of cases occur in overweight or
obese individualsSimilar complications.Dietary
change and exercise can reverse the condition.
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• Pancreatic hormones and fat
• insulin promotes storage of glucose into
  glycogen and fatty acids into fat
• glucagon promotes conversion of glycogen to
  glucose and fat to fatty acids for use
• Regulatory systems are quite complex with respect
  to energy utilization, storage , and
  appetite/satiation signals.

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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 --gt triggers hypothalamus
to secrete NPY (neuropeptide Y) to increase
eating.High level in blood --gt 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 (low leptin)- 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 (high
leptin)- 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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Zone appears to be set based on genetic
predisposition and early environmental
characteristics. 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 gt 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 gt 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!