Hello, my name is Jeff Friedman.
I'm a professor at the Howard Hughes Medical Institute
and at Rockefeller University. And I'm pleased to
be part of the iBiology series.
Today I'm going to tell you about our research
into the causes of obesity
and the discovery of the hormone leptin.
One of the problems our science addresses
is obesity. And at some level we'd like to
understand why it is that some
individuals have the appearance of
the child on the left and other people have the
appearance on the right.
You ask the average person why
the difference? And most people would say, well
the individual on the left eats too much.
Well, that would be true, but it would ignore
the deeper question of why does the
individual on the left eat too much?
And I'd like to try to answer that question
for you today.
Now there are several general
reasons to explain why some individuals
might eat more than others.
One possibility is to suggest that
the obese lack a level of willpower
that's more evident in lean people.
I find that point of view is more often
favored by lean people. Second possibility
is to suggest that we live in a modern
environment that predisposes to obesity.
And a third possibility would be to suggest
that body weight is controlled by
biological factors and genes.
In the interest of time, I'm not going
to discuss the relative contributions
of willpower and environment,
but tell you, in fact, there's substantial
evidence that genes play a dominant
role to control body weight.
There's a number of ways to test
the genetic contributions to a particular trait.
The standard way to do so is to systematically
compare twin pairs.
Identical twins share all of their genes,
fraternal twins only share half their genes.
So if identical twins are more alike
for a particular trait, then
non-identical twins we can calculate
the genetic contribution to that trait.
If you do this for obesity, what you find
is that obesity is as or more
heritable than any trait that's yet been studied,
with the exception of height.
In fact, obesity is more heritable than
many traits that we commonly consider have a genetic
basis, including schizophrenia, diabetes,
hypertension, alcoholism, and heart disease.
In fact, we can calculate based on
this that about 70-80% of the variation in body
weight can be ascribed to genetic factors.
Now to show you the potency of
these genetic factors to control weight,
I would like to tell you about a case report.
This is the child whose image I began by
showing you, this child was of normal weight
at birth but began to develop morbid obesity
very early in life. His parents reported
intense hyperphagia, intense appetite, to the point where
they even padlocked the refrigerator
to keep the child from getting free access
to food. Despite this, the child kept getting
fatter and at the age of 4, he weighed
90lbs and was already pre-diabetic.
Now this child had a similarly effected
8 year old cousin who weighed over 200lbs.
Both these children came from an inbred family
and often times when you seen an extreme
phenotype in an inbred family, in this case,
as a result of a first cousin marriage,
it's a result of a genetic alteration.
So Steve O'Rahilly and colleagues
suggested that perhaps this child was
obese as the result of a mutation
in a particular gene. And they hypothesized
that this child might be missing a hormone
leptin that was first identified by my laboratory.
Leptin is a hormone made by fat tissue
that's secreted into the blood where it circulates,
ultimately acting on the brain to regulate
food intake. In the absence of leptin,
animals eat more and so, O'Rahilly suggested
that perhaps this child was missing the hormone leptin.
They tested and indeed, the child was
missing leptin. So they decided to now take leptin
that was made in the laboratory and give it back
to this child. And what you can see is
that the child from between the ages of 4
and 6, lost a substantial amount of weight, despite
getting taller. In addition, the child
ate less. Before the first leptin injection
he ate 2000 calories in a single meal,
after a few leptin injections, the child now
ate a 180 calories at the same meal,
which is the appropriate number of calories for a child
of that age and size.
In this case the child was obese
because of a defect in the hormone leptin,
without leptin no signal is ever generated
that there are adequate fat stores.
This is a stimulus to eat more and this child
kept eating, kept getting fatter, without ever making
the signal to shut the system off.
And now here's a picture of the child
at the age of 8, it's the same child I began
by showing you a picture of. So this child
was obese, not as a lack of will power
or a toxic environment; this child was obese
because a lack of a hormone leptin.
Studies of this child and other individuals
has now suggested that body weight is regulated
by a hormonal loop, of which leptin
is an important component.
At our stable weight, food intake
equals energy expenditure and we make a particular
amount of leptin. Now imagine if that
mass falls after a diet, leptin level would fall.
A low leptin level will be provide a stimulus
to eat more, much as the same as the case
of the untreated leptin-deficient child,
and now, an individual will have a potent
stimulus to their appetite until such time
as their fat mass and leptin level returns
to the starting point.
Conversely, if you overeat for a period
of time, binge-eating, fat mass goes up and leptin
levels go up with it. This will suppress
appetite, again, until such time the fat mass
and leptin level return to the starting point.
So because leptin is made in proportion
to fat mass, it provides a signal
that can then control food intake and
the response to weight loss or weight gain.
And what this system does in a sense
is set up a biological response that
resists weight change in either direction.
If you lose fat mass, leptin level falls
and there's stimulus to gain weight.
If you gain fat mass, leptin level rises
and that suppresses appetite. And by this
mechanism, body weight can be maintained within
a relatively narrow range.
Now, if you hear all of this and find that there
was an undiscovered hormone circulating in the blood of animals
and humans, it seems rather mysterious
to consider how this hormone was identified.
So I'd like to now tell you about how
I became interested in this hormone and how
it was discovered.
My interest in this area began with
an interest in behavior. How molecules control behavior
and my first interest centered on another
hormone that's said to regulate appetite,
CCK. Cholecystokinin is made by
endocrine cells in your intestine in response to
food. When food is present
inside your gut, CCK is secreted
into the blood and it stimulates
the contraction of your gallbladder and
secretion of enzymes by your pancreas
that aid in digestion.
And this was the situation in 1968,
prior to the work of Smith and Gibbs, who also
showed that CCK can suppress appetite.
They suggested in fact, that this intestinal hormone
when it's secreted, not only helps aid digestion
but also circulates in the blood and acts on
the brain to shut off a meal.
Made perfect sense, excitement in this area
was amplified when a few years later,
CCK was also found in the brain
by a group led by Graham Dockray.
This then suggested that perhaps
appetite and body weight are regulated
by a hormone that is expressed in both
the gut and the brain. And that the levels
peripherally synthesized in brain synthesized
CCK might control food intake and
body weight. And this was referred to at the time
as the "gut-brain" axis.
Interest in this area was amplified even further
in 1970 when Straus and Yalow reported
that the levels of CCK were reduced in the brains
of a strange genetically obese mouse, known as the ob mouse.
The ob mouse as a result of a defect in a single
gene, and Yalow and Straus suggested that that
affected gene might be CCK, this endogenous
appetite suppresant. With a lower level
of the endogenous appetite suppressant,
the animals might eat more.
Well, this is a picture of the ob mouse.
The animal on the far right is an ob mouse,
and the animal second from the right
is a lean littermate of that animal.
The only defect between the ob mouse
and its sibling littermate is a defect
in a single gene. That single genetic defect
leads the ob animal to eat more, more around
less, ultimately weigh three times as much
and having five times as much fat
as the sibling littermate.
And as I mentioned, Yalow suggested that
perhaps this animal overate
because it was missing CCK,
this endogenous appetite suppressant.
The only problem with this idea
is that it very might well be wrong.
And this had to do with the fact that
the person I was working with at the time,
Bruce Schneider, published a contemporaneous report
showing that the levels of CCK
in brain were no different in ob mice versus
their lean littermates.
And so, we and others wondered whether or not
CCK was the defective gene
in the ob animals.
Well, one of the first things we did
at the time was to clone the CCK
gene. And the idea was to clone
the CCK gene and see where on the
chromosome it mapped, whether it mapped
near the location of the ob gene.
We quickly found that CCK mapped to the
distal end of Chromosome 9.
This is a map of Chromosome 9 with a variety
of genes that map there. The only
problem was that the ob gene didn't map
to Chromosome 9, it mapped to Chromosome 6.
So these data excluded the possibility
that CCK was the ob gene.
And raised the question, well if it's not
CCK, what is it?
In the 1980s when we did this work,
a new technology was emerging that allowed
one to identify defective genes,
not based on knowledge of their function,
but simply based on detailed knowledge
of the chromosomal location of that gene.
This methodology was known as positional
cloning, and we set out then to identify
the ob gene using positional cloning.
This required identifying genes in the region
of the chromosome where ob was known to map.
And one day, on a Friday, we found
a gene in the region of ob that was expressed only
in fat tissue. This is a Northern blot, it's a way at the time
of measuring RNA levels and only
fat tissue had an RNA for this gene,
which we knew mapped near the ob gene.
The next step was to ask, is
this gene defective in strains of mice
that are genetically obese?
And indeed it was.
If you look here at lane 2, that's fat tissue
from a normal mouse. Lane 3 is fat
tissue from an ob mouse of the same
strain. That strain fails to make the ob
RNA and that's why it's fat.
Lane 4 is RNA is fat tissue of a different strain
of mouse and lane 5 is RNA from
the obese animal from that same strain.
In this case, increased levels of RNA are produced
and that's because the RNA produces
a defective protein. The animal then makes more and more
RNA as a means of trying to compensate,
unsuccessfully, because the RNA makes a defective
protein. Well, the demonstration that
this gene was defective in two
different obese strains of mice
confirmed that we had in fact identified
the defective gene, and this was published
to some fanfare in 1994 with this image
of an obese mouse outweighing two
of its sibling littermates.
Shortly after identifying the ob gene,
subsequent studies revealed, in fact,
that the defective gene encoded this hormone
leptin. It's the hormone made by fat
tissue that regulates appetite by
acting on brain centers.
One of the key experiments was done by
collaborators Jeff Halaas and Ketan Gajiwala and Steve
Burley, together we showed that if you inject
saline into an ob animal nothing happens,
they stay obese. But if you inject leptin
made in the laboratory, animals normalize
their phenotype. Much the same as O'Rahilly
and colleagues later showed for this leptin
deficient child.
Now leptin mutations are quite rare,
there are only a few dozen such mutations
in the world, which is characteristic of hormones
which are poor targets for mutations.
But we now know that perhaps 10-15%
of morbid obesity is the result of
single gene defects in other genes
in the neural circuit on which leptin acts.
And so this has provided a great stimulus
in research into the causes of obesity,
and tells us now that obesity is very often
a result of specific genetic defects.
I suspect that we'll identify ever more
of these defects now, with advances in DNA
sequencing and other new technologies.
And so I think research in this
area has been greatly stimulated by the
identification of leptin and the realization
that obesity can be the result of genetic defects
in a neural circuit that regulates food intake
and body weight.