Metabolic Integration 2: Energy balance, the diabesity epidemic, biochemistry of nutrition and exerc

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Metabolic Integration 2Energy balance, the
diabesity epidemic, biochemistry of nutrition
and exercise
Bioc 460 Spring 2008 - Lecture 41 (Miesfeld)
Metformin
Leptin is released from visceral fat and controls
neuronal signaling in the brain
James Neel, M.D., proposed the term thrifty
gene to explain the role of genes and lifestyle
in diabesity
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Metformin
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Key Concepts in Metabolic Integration

• Energy balance refers to the metabolic state in
  which the Calories contained in the metabolic
  fuel you consume are equal to the Calories you
  expend as a result of chemical reactions in the
  body, muscle contraction, and thermogenesis.
• Leptin is a peptide hormone that is secreted by
  visceral adipose tissue in proportion to the
  amount of stored lipid. Since leptin inhibits
  appetite and increases energy expenditure, it may
  represent a molecular fat-o-stat.
• Choosing oils that low in saturated fats, and
  carbohydrates with a low glycemic index, can add
  value to your food. Metabolic regulation and
  signal transduction through AMPK and PPAR appear
  to be key components of this mechanism.
• Studies have suggested that regular moderate to
  intense physical exercise can stimulate signaling
  pathways in muscle cells that reduce the risks of
  cardiovascular disease even if this regimen does
  result in significant weight loss.

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The Diabesity Epidemic
Almost two-thirds of adults in the United States
are either overweight (BMI of 25-30) or obese
(BMI gt30), and nearly one-third of children ages
6-18 fit these same descriptions. Moreover, the
incidence of type 2 diabetes in children has
increased ten-fold in the last 15 years.
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Metabolic Energy Balance
The concept of energy balance can be used to
explain how energy input (food calories) and
energy expenditure (basal metabolism, physical
activity, exercise) alter metabolic homeostasis
to bring about a measurable weight gain or weight
loss as reflected in the amount of stored fat in
the body. By consuming an extra 115
calories/day for a month (total of 3500
calories), you will add one pound of stored fat
to your body.
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The Thrifty Gene Hypothesis
James Neel, a University of Michigan physician
scientist proposed his thrifty gene hypothesis to
explain the genetic basis for obesity and
diabetes. Neel proposed that humans contain gene
variants (thrifty genes) that favor individuals
with a capacity to store extra fat during times
of feast as a way to prolong survival during
times of famine.
Pima Indians of southern Arizona have rates of
obesity and type 2 diabetes that are among the
highest in the world. However, a second
population of Pima Indians in northern Mexico
that are genetically similar and speak the same
language, weigh on average 57 pounds less than
their Arizona relatives and the incidence of
diabetes is almost nine times lower.
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The Thrifty Gene Hypothesis
Neel argued that while this genetic background
was a good thing to have when humans depended on
a hunter and gatherer lifestyle, these same
thrifty gene variants become disease genes in a
modern society where high fat foods and sedentary
lifestyles are common. While it is still not
clear what the most likely candidates are for
these thrifty genes, key suspects include
signaling proteins that control metabolic
homeostasis and genes encoding glucose and lipid
metabolizing enzymes.
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Leptin Controls Appetite and Energy Expenditure
A major breakthrough in obesity research came in
1994 when Jeffery Friedman and his colleagues at
Rockefeller University identified a gene mutation
in a strain of obese mice called OB (obese). The
mutant gene was named leptin after the Greek word
leptos which means thin. Friedman's lab
demonstrated that the molecular defect in a
second strain of obese mice called DB (diabetic),
was in fact due to a mutation in the leptin
receptor. The phenotypes of OB and DB mice are
very similar in that both are grossly overweight
and have elevated levels of glucose and insulin
in the serum due to insulin-resistance.
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Leptin may be a type of fat-o-stat
Following a period of positive energy balance,
fat stores increase, which results in elevated
serum levels of leptin and subsequent activation
of neuronal signals that decrease appetite and
increase energy expenditure. This returns the
body to its normal set point weight.
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Leptin may be a type of fat-o-stat
Leptin receptor activation in the hypothalamus
controls appetite and energy expenditure through
a complex hierarchical neuronal signaling scheme
that involves first order and second order
neurons. Basically, leptin activates neurons
in the brain that relay the message to stop
eating and start exercising, while at the same
time, inhibiting neurons that normally relay the
message to eat more and exercise less. Insulin
has a similar effect on these same neurons. Two
peptide hormones synthesized in the stomach
(ghrelin), and small intestine (PYY3-36), also
control appetite and energy expenditure. Ghrelin
signals hunger when there is no food in the
intestine, whereas, PYY3-36 signals full when
food is in the intestine.
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Based on the function and localized secretion of
ghrelin and PYY3-36, why is it good advice to eat
slowly if you are trying to lose weight?
Why does it make sense that leptin and insulin
have the same effect on neuronal signaling, what
signal are they each sending to the brain?
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Metabolic link between obesity and type 2 diabetes
Insulin-resistant type 2 diabetes is distinct
from type 1 diabetes in that type 1 diabetes is
due to insufficient insulin production by the
pancreatic ? cells, whereas, type 2 diabetes is
characterized by desensitization of insulin
receptor signaling. As shown by a glucose
tolerance test, both type 1 and type 2 diabetes
are associated with elevated serum glucose levels
and abnormal glucose clearance kinetics, however,
only type 1 diabetes has a normal response to
insulin treatment.
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Metabolic link between obesity and diabetes
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Metabolic link between obesity and diabetes
Research over that past twenty years have
implicated that both genes and environment
contribute to the development of obesity and type
2 diabetes. In many cases, obesity leads to
prediabetic symptoms that are characterized by
elevated levels of serum glucose (hyperglycemia)
and over-production of insulin (insulinaemia).
If this condition persists, it will lead to
insulin-resistance, and eventually, clinical type
2 diabetes. Note that type 2 diabetes can also
be initiated independent of obesity as a
consequence of genetic defects that alter insulin
signaling pathways.
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Treatment of Type 2 Diabetes
Four classes of drugs have been developed to
treat type 2 diabetes 1) Migitol inhibits the
intestinal ?-glucosidase to reduce carbohydrate
uptake in the small intestine. 2) Glipizide is a
sulfonylurea drug that inhibits pancreatic
ATP-dependent K channel and thereby stimulates
insulin release. 3) Metfomin is an activator of
AMP-activated kinase (AMPK) 4)
Thiazolidinediones (TZDs) are PPAR agonist that
activate lipid metabolism in adipocytes and
increase insulin sensitivity.
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Treatment of Type 2 Diabetes
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Biochemistry of Nutrition and Exercise
The three primary factors influencing metabolic
homeostasis are genetic inheritance, nutrition,
and exercise. Maintaining a healthy weight
significantly lowers the risk of type 2 diabetes
and cardiovascular disease, and moreover, recent
studies have suggested that some types of cancers
may also be linked to obesity. Although there
is no escaping the biochemical reality that
energy balance determines body weight, not all
foods of equal calories provide the same
nutritional value, and therefore what you eat,
can be almost as important as how much you eat.
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Strategies to Lose Weight
One of the oldest drugs used to induce weight
loss is ephedrine which acts indirectly to
stimulate adrenergic receptor signaling through
enhanced release of noradrenaline, a
catecholamine signaling molecule. The pancreatic
lipase inhibitor orlistat, which goes by the
pharmaceutical name Xenical, can be taken in pill
form before a meal to limit fat absorption. By
inhibiting the hydrolytic action of pancreatic
lipase in the small intestine, dietary
triglycerides pass through the gastrointestinal
tract and are excreted. A complementary
strategy is to replace fats in processed foods
with a fat substitute such as olestra that cannot
be digested. Olestra is a sucrose molecule that
has been chemically modified to contain up to
eight fatty acyl groups.
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Strategies to Lose Weight
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Most Diets Work About the Same in the End
Forty participants started on each diet, but
14-20 people dropped out. How might this affect
the data analysis in terms of effectiveness?
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Good Calories and Bad Calories
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Good Calories and Bad Calories
The glycemic index (GI) is a numerical value that
indicates how quickly glucose is released into
the blood after eating different types of
carbohydrate-containing foods. Low GI is better
for you because it prevents a spike in insulin
levels which would lead to fat synthesis.
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Biochemistry of Nutrition and Exercise
Achieving energy balance requires that both
Caloric intake and Caloric expenditure be equal.
Considering that an average person burns about 70
Calories/hour when at rest (1700 Calories/day),
one would need to expend another 300 Calories/day
through physical activity to maintain energy
balance on a 2000 Calorie/day diet. This could
be done by combining a number of passive
activities such as walking briskly to work (170
Calories), taking the stairs instead of the
elevator (240 Calories), or even vacuuming (130
Calories). In ancient times, the energy
expenditure required to obtain food was
sufficient to maintain energy balance, and
therefore, high levels of physical activity was a
part of daily life.
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Biochemistry of Nutrition and Exercise
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Exercise is Beneficial Even Without Weight Loss
Group 1 did not exercise at all, group 2
performed exercise three times a week at moderate
intensity, and group 3 performed the same
exercise regimen but at high intensity. Group 3
had the biggest metabolic benefit.
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AMPK Signaling is Activated by Exercise
One of the most important mechanisms to provide a
steady supply of ATP for muscle contraction is
exercised-induced activation of AMPK
signaling. AMPK alters metabolic flux through
energy converting pathways to increase ATP
production. AMPK is a heterotrimeric protein
that is highly conserved in eukaryotes and
consists of a catalytic ? subunit, a regulatory ?
subunit that binds AMP, and the ? subunit which
functions as a molecular scaffold.
Exercise-induced increases in the AMP/ATP
ratio (low energy charge) leads to AMP binding to
the ? subunit. This leads to a conformational
change in the complex that facilities
phosphorylation of a threonine residue (Thr172)
in the catalytic domain of the ? subunit.
Numerous AMPK target proteins have been
identified in skeletal muscle cells.
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AMPK Signaling is Activated by Exercise
What mechanisms would reduce AMPK activity when
exercise is over and the ATP levels in the muscle
return to normal?