The readings include most answers. I also found the following sources useful:
Gut Peptides: Targets for Antiobesity Drug Development? by Timothy H. Moran and
Megan J. Dailey Endocrinology Vol. 150, No. 6 2526-2530
http://endo.endojournals.org/cgi/content/full/150/6/2526
Group 1: Leptin
Basic Science
a. What is leptin? Leptin is a protein hormone, product of the ob gene that is expressed
in fat cells.
b. What does leptin normally do? Leptin is involved in weight regulation. It signals to
the receptors in the hypothalamus. It provides a long-term signal about the amount of fat
a person has. (More fat = more leptin; less fat = less leptin.) The hormone helps provide a
signal that an individual needs to eat (and store up energy) if the fat levels are low. This
is useful from an evolutionary sense.
c. What is the phenotype of “knockout” mice that lack
leptin? These mice (ob gene) are obese! (See mouse on right.)
d. What is the phenotype of mice that lack leptin receptors?
These mice are also obese (db gene) since they are in the same
pathway.
e. What happens when you give leptin supplements to mice
lacking leptin?
“A dramatic reduction in food intake within a few days, and to
roughly a 50% reduction in body weight within a month. Weight
loss resulting from administration of leptin appears to result from
a combination of at least two fundamental effects:
 Decreased hunger and food consumption
 Increased energy expenditure”
f. What happens when you give leptin to mice lacking the leptin receptor?
Nothing. With no receptor to receive the signal, increased leptin will still not make the
pathway work.
Applied Research
g. What happens when you give obese humans leptin?
“When Amgen sponsored a large clinical trial of leptin, however, few participants lost
weight.
But 15 to 20 percent of the obese people [in the study] did in fact lose significant
amounts of weight.”
h. What humans can benefit most from leptin supplements? People who lack leptin.
Most obese people don’t have a problem with making leptin (since fat produces leptin).
These people are probably leptin resistant. There are some people with the analogous ob
mutation and they do not produce leptin. Providing them leptin would decrease their
weight.
i. Are leptin supplements a wonder drug? No, the large scale Amgen studies show that
it will not be because leptin deficiency is a rare cause of obesity. It will be useful for a
subset of patients, but this would not be a “blockbuster” drug for a pharmaceutical
company.
Group 2: Peptide YY (PYY)
Basic Science
a. What is PYY? A small peptide hormone, secreted from the gut. It peaks a few hours
after a meal and then declines.
b. What does it normally do? PYY dampens hunger.
c. What is the phenotype of “knockout” mice that lack PYY? The knockouts were
obese and loved to eat: by 10 weeks of age, PYY knockout mice weighed about 37.5%
more than normal mice and had about 12% more body fat. A high-protein diet did not
curb their hunger.
d. What happens when you give mice that lack PYY a supplement of PYY? Giving
PYY3-36 to the knockout mice led to a drastic reduction in their eating habits and
consequently their body fat and body weight.
e. What happens when you give normal mice a PYY supplement? Little or no change
–
in these control (wildtype) mice.
f. The PYY gene has been knocked out by three different researchers. What is the
controversy about their phenotypes? The mice from the three groups do not all have
the same phenotype. Replicating results is the basis of science. The reason they don’t
have the phenotype is likely complex based on the methodology used.
Applied Science
g. What does this article suggest is the reason that eating a high protein and not a
high fat diet keeps an individual satisfied longer? High protein diets lead to a higher
increase of PYY in humans (and rodents). More PYY = more satisfied for longer.
h. What happens when PYY is injected into humans? When injected into humans it
decreases hunger for 12 hours or more.
i. Might PYY be a new anti-obesity wonder drug? There are still elements of
controversy since not all results from scientists are the same. While it is not yet a wonder
drug, it may still show promise with more research.
Group 3: Ghrelin and Surgery
Sometimes science works in reverse. For example, gastric bypass surgery works for
obese patients because their appetite decreases. Studies now suggest the
physiological reason for this. What is it? Ghrelin levels are very low and remain low
(don’t cycle through the day) unlike individuals simply dieting. The research team
believes the cells in the stomach that produce ghrelin become inactive when they are no
longer exposed to food in the gut. "We think ghrelin cells 'go to sleep' when they're
deprived of contact with ingested nutrients," Cummings said.
The ghrelin hormone normally binds a receptor that provides what signal to the
brain? It is a “hunger hormone.” When levels are high and the individual would feel the
need to eat. The hormone leads to fat storage and a decrease in energy expenditure. This
is in contrast to the other two hormones, PYY and leptin, that cause a decrease in hunger
when their levels are high.
If a pharmaceutical could be developed, what effect would it have to have on
ghrelin. Would it increase or block it? Think of two different ways to design this
drug (i.e. what would it bind to?) Draw these:
The goal would be to decrease ghrelin signaling. This can be done by either inhibiting
ghrelin directly so that it cannot bind its receptor, or the receptor itself could be the drug
target. (Both have been tried and the receptor seems to be the more promising approach
for pharmaceuticals.)
What would you predict would be the phenotype of mice that have the ghrelin
receptor gene deleted from their genome?
Students may have different guesses here such as skinny or no effect. Studies show that
deleting ghrelin receptor signaling leads to mice that are resistant to obesity when fed
high fat diets. The control wild-type mice gain weight when fed high fat diets.
What has been the problem with previous anti-obesity drugs that made it to market,
such as fen-phen?
These drugs cause hypertension (high blood pressure) and heart valve defects in some
individuals.
Whole class conclusions
There are many genes involved in the obesity trait. Obesity is a _polygenic__ trait.
How is obesity defined?
The NIH uses body mass index. Encourage students to calculate their own after class.
Show students the BMI calculator at: http://www.nhlbisupport.com/bmi/
NIH defined BMI Categories:
Underweight = < 18.5
Normal weight = 18.5 – 24.9
Overweight = 25 – 29.9
Obesity = BMI of 30 or greater
(To avoid personal discussions, you might want to ask them a question such as, how
much would a 5 foot 6 inch female need to weigh to be considered obese?)
If we wanted to “design” an obese person, what would we want to do to each of these
hormone levels? (Raise or lower?)
PYY – decrease
Leptin – decrease
Ghrelin – increase
If we wanted to “design” a skinny person, what would we want to do to each of these
hormone levels? (Raise or lower?)
PYY – increase
Leptin – increase
Ghrelin – decrease
Does basic science always translate into practical applications? If not, is it a waste?
No. Basic science doesn’t always translate. For example, the leptin mouse studies
suggested a better application of leptin supplments in obese humans. However, basic
science is not a waste! Many wonderful discoveries come out of basic research with no
initial intent to make the knowledge applicable. When the knowledge is realized to be
useful for some application, we then call this translational research.
Aside from a few select obese people in the world with severe genetic mutations,
what is the best “medicine” for most people to keep a healthy weight?
Exercise, ELF (eat less food), and sleep.
(There are various studies examining sleep. One example: studies with ghrelin show that
this hormone is highest at night. If you are sleeping, you can’t give into the hunger urge.
Obese people may be more likely to wake and eat as ghrelin peaks.)