Download Lecture 33

Metabolic Integration 2:
Energy balance, the “diabesity” epidemic,
biochemistry of nutrition and exercise
Bioc 460 Spring 2008 - Lecture 41 (Miesfeld)
Metformin
James Neel, M.D., proposed
the term “thrifty gene” to
explain the role of genes and
lifestyle in “diabesity”
Leptin is released
from visceral fat and
controls neuronal
signaling in the brain
Metformin
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.
The “Diabesity” Epidemic
Almost two-thirds of adults in the United States are either overweight
(BMI of 25-30) or obese (BMI >30), 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.
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.
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.
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.
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.
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.
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.
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?
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.
Metabolic link between obesity and diabetes
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.
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.
Treatment of Type 2 Diabetes
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.
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.
Strategies to Lose Weight
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?
Good Calories and Bad Calories
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.
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.
Biochemistry of Nutrition and Exercise
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.
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.
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?