The Causes of Obesity and the Discovery of Leptin

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00:00:06.19 Hello, my name is Jeff Friedman.
00:00:09.26 I'm a professor at the Howard Hughes Medical Institute
00:00:12.03 and at Rockefeller University. And I'm pleased to
00:00:13.27 be part of the iBiology series.
00:00:15.25 Today I'm going to tell you about our research
00:00:18.02 into the causes of obesity
00:00:19.17 and the discovery of the hormone leptin.
00:00:22.14 One of the problems our science addresses
00:00:26.21 is obesity. And at some level we'd like to
00:00:29.25 understand why it is that some
00:00:31.03 individuals have the appearance of
00:00:33.19 the child on the left and other people have the
00:00:36.00 appearance on the right.
00:00:37.14 You ask the average person why
00:00:40.26 the difference? And most people would say, well
00:00:42.28 the individual on the left eats too much.
00:00:45.11 Well, that would be true, but it would ignore
00:00:48.00 the deeper question of why does the
00:00:50.11 individual on the left eat too much?
00:00:51.21 And I'd like to try to answer that question
00:00:54.13 for you today.
00:00:56.01 Now there are several general
00:00:57.16 reasons to explain why some individuals
00:00:59.05 might eat more than others.
00:01:01.03 One possibility is to suggest that
00:01:02.29 the obese lack a level of willpower
00:01:04.21 that's more evident in lean people.
00:01:06.21 I find that point of view is more often
00:01:08.24 favored by lean people. Second possibility
00:01:11.14 is to suggest that we live in a modern
00:01:13.18 environment that predisposes to obesity.
00:01:16.09 And a third possibility would be to suggest
00:01:18.13 that body weight is controlled by
00:01:20.19 biological factors and genes.
00:01:22.15 In the interest of time, I'm not going
00:01:24.26 to discuss the relative contributions
00:01:26.15 of willpower and environment,
00:01:28.12 but tell you, in fact, there's substantial
00:01:30.20 evidence that genes play a dominant
00:01:32.14 role to control body weight.
00:01:34.11 There's a number of ways to test
00:01:36.22 the genetic contributions to a particular trait.
00:01:38.24 The standard way to do so is to systematically
00:01:41.05 compare twin pairs.
00:01:44.04 Identical twins share all of their genes,
00:01:46.04 fraternal twins only share half their genes.
00:01:49.04 So if identical twins are more alike
00:01:51.19 for a particular trait, then
00:01:53.00 non-identical twins we can calculate
00:01:55.18 the genetic contribution to that trait.
00:01:58.21 If you do this for obesity, what you find
00:02:01.04 is that obesity is as or more
00:02:03.09 heritable than any trait that's yet been studied,
00:02:06.00 with the exception of height.
00:02:07.20 In fact, obesity is more heritable than
00:02:10.16 many traits that we commonly consider have a genetic
00:02:12.27 basis, including schizophrenia, diabetes,
00:02:15.09 hypertension, alcoholism, and heart disease.
00:02:18.01 In fact, we can calculate based on
00:02:20.02 this that about 70-80% of the variation in body
00:02:23.16 weight can be ascribed to genetic factors.
00:02:26.09 Now to show you the potency of
00:02:28.07 these genetic factors to control weight,
00:02:30.04 I would like to tell you about a case report.
00:02:32.03 This is the child whose image I began by
00:02:34.22 showing you, this child was of normal weight
00:02:36.27 at birth but began to develop morbid obesity
00:02:39.03 very early in life. His parents reported
00:02:42.17 intense hyperphagia, intense appetite, to the point where
00:02:46.09 they even padlocked the refrigerator
00:02:48.01 to keep the child from getting free access
00:02:50.13 to food. Despite this, the child kept getting
00:02:53.05 fatter and at the age of 4, he weighed
00:02:55.23 90lbs and was already pre-diabetic.
00:02:59.01 Now this child had a similarly effected
00:03:01.13 8 year old cousin who weighed over 200lbs.
00:03:06.21 Both these children came from an inbred family
00:03:09.22 and often times when you seen an extreme
00:03:12.00 phenotype in an inbred family, in this case,
00:03:14.11 as a result of a first cousin marriage,
00:03:16.03 it's a result of a genetic alteration.
00:03:19.01 So Steve O'Rahilly and colleagues
00:03:21.12 suggested that perhaps this child was
00:03:24.03 obese as the result of a mutation
00:03:25.26 in a particular gene. And they hypothesized
00:03:28.16 that this child might be missing a hormone
00:03:31.05 leptin that was first identified by my laboratory.
00:03:34.00 Leptin is a hormone made by fat tissue
00:03:36.25 that's secreted into the blood where it circulates,
00:03:39.10 ultimately acting on the brain to regulate
00:03:42.29 food intake. In the absence of leptin,
00:03:46.27 animals eat more and so, O'Rahilly suggested
00:03:50.05 that perhaps this child was missing the hormone leptin.
00:03:52.26 They tested and indeed, the child was
00:03:54.21 missing leptin. So they decided to now take leptin
00:03:58.04 that was made in the laboratory and give it back
00:04:00.15 to this child. And what you can see is
00:04:02.16 that the child from between the ages of 4
00:04:04.13 and 6, lost a substantial amount of weight, despite
00:04:07.10 getting taller. In addition, the child
00:04:10.01 ate less. Before the first leptin injection
00:04:12.16 he ate 2000 calories in a single meal,
00:04:14.20 after a few leptin injections, the child now
00:04:17.04 ate a 180 calories at the same meal,
00:04:20.01 which is the appropriate number of calories for a child
00:04:22.16 of that age and size.
00:04:23.28 In this case the child was obese
00:04:27.02 because of a defect in the hormone leptin,
00:04:29.06 without leptin no signal is ever generated
00:04:31.13 that there are adequate fat stores.
00:04:33.02 This is a stimulus to eat more and this child
00:04:36.01 kept eating, kept getting fatter, without ever making
00:04:39.15 the signal to shut the system off.
00:04:41.19 And now here's a picture of the child
00:04:43.09 at the age of 8, it's the same child I began
00:04:45.17 by showing you a picture of. So this child
00:04:48.06 was obese, not as a lack of will power
00:04:50.24 or a toxic environment; this child was obese
00:04:53.05 because a lack of a hormone leptin.
00:04:56.02 Studies of this child and other individuals
00:04:59.04 has now suggested that body weight is regulated
00:05:01.07 by a hormonal loop, of which leptin
00:05:03.11 is an important component.
00:05:05.03 At our stable weight, food intake
00:05:08.05 equals energy expenditure and we make a particular
00:05:10.25 amount of leptin. Now imagine if that
00:05:13.20 mass falls after a diet, leptin level would fall.
00:05:18.13 A low leptin level will be provide a stimulus
00:05:21.13 to eat more, much as the same as the case
00:05:24.02 of the untreated leptin-deficient child,
00:05:26.03 and now, an individual will have a potent
00:05:28.23 stimulus to their appetite until such time
00:05:31.10 as their fat mass and leptin level returns
00:05:33.06 to the starting point.
00:05:34.19 Conversely, if you overeat for a period
00:05:37.02 of time, binge-eating, fat mass goes up and leptin
00:05:41.00 levels go up with it. This will suppress
00:05:43.07 appetite, again, until such time the fat mass
00:05:45.28 and leptin level return to the starting point.
00:05:48.01 So because leptin is made in proportion
00:05:50.26 to fat mass, it provides a signal
00:05:52.25 that can then control food intake and
00:05:55.25 the response to weight loss or weight gain.
00:05:58.17 And what this system does in a sense
00:06:00.13 is set up a biological response that
00:06:02.18 resists weight change in either direction.
00:06:04.09 If you lose fat mass, leptin level falls
00:06:07.02 and there's stimulus to gain weight.
00:06:08.20 If you gain fat mass, leptin level rises
00:06:11.07 and that suppresses appetite. And by this
00:06:14.17 mechanism, body weight can be maintained within
00:06:16.28 a relatively narrow range.
00:06:18.24 Now, if you hear all of this and find that there
00:06:21.20 was an undiscovered hormone circulating in the blood of animals
00:06:25.04 and humans, it seems rather mysterious
00:06:28.16 to consider how this hormone was identified.
00:06:31.02 So I'd like to now tell you about how
00:06:32.28 I became interested in this hormone and how
00:06:35.01 it was discovered.
00:06:36.12 My interest in this area began with
00:06:38.27 an interest in behavior. How molecules control behavior
00:06:42.11 and my first interest centered on another
00:06:46.00 hormone that's said to regulate appetite,
00:06:47.20 CCK. Cholecystokinin is made by
00:06:51.25 endocrine cells in your intestine in response to
00:06:54.01 food. When food is present
00:06:56.05 inside your gut, CCK is secreted
00:06:58.08 into the blood and it stimulates
00:07:00.19 the contraction of your gallbladder and
00:07:02.28 secretion of enzymes by your pancreas
00:07:05.10 that aid in digestion.
00:07:06.25 And this was the situation in 1968,
00:07:09.22 prior to the work of Smith and Gibbs, who also
00:07:12.16 showed that CCK can suppress appetite.
00:07:15.10 They suggested in fact, that this intestinal hormone
00:07:20.00 when it's secreted, not only helps aid digestion
00:07:22.21 but also circulates in the blood and acts on
00:07:25.08 the brain to shut off a meal.
00:07:27.25 Made perfect sense, excitement in this area
00:07:31.02 was amplified when a few years later,
00:07:33.20 CCK was also found in the brain
00:07:36.09 by a group led by Graham Dockray.
00:07:38.13 This then suggested that perhaps
00:07:40.18 appetite and body weight are regulated
00:07:43.05 by a hormone that is expressed in both
00:07:46.05 the gut and the brain. And that the levels
00:07:48.09 peripherally synthesized in brain synthesized
00:07:52.04 CCK might control food intake and
00:07:55.02 body weight. And this was referred to at the time
00:07:58.00 as the "gut-brain" axis.
00:07:59.09 Interest in this area was amplified even further
00:08:02.08 in 1970 when Straus and Yalow reported
00:08:05.08 that the levels of CCK were reduced in the brains
00:08:08.02 of a strange genetically obese mouse, known as the ob mouse.
00:08:12.19 The ob mouse as a result of a defect in a single
00:08:16.10 gene, and Yalow and Straus suggested that that
00:08:19.13 affected gene might be CCK, this endogenous
00:08:21.24 appetite suppresant. With a lower level
00:08:24.19 of the endogenous appetite suppressant,
00:08:26.06 the animals might eat more.
00:08:28.24 Well, this is a picture of the ob mouse.
00:08:30.24 The animal on the far right is an ob mouse,
00:08:34.03 and the animal second from the right
00:08:38.26 is a lean littermate of that animal.
00:08:40.21 The only defect between the ob mouse
00:08:42.22 and its sibling littermate is a defect
00:08:44.28 in a single gene. That single genetic defect
00:08:47.26 leads the ob animal to eat more, more around
00:08:50.20 less, ultimately weigh three times as much
00:08:52.27 and having five times as much fat
00:08:54.28 as the sibling littermate.
00:08:56.11 And as I mentioned, Yalow suggested that
00:08:59.02 perhaps this animal overate
00:09:01.04 because it was missing CCK,
00:09:03.03 this endogenous appetite suppressant.
00:09:05.02 The only problem with this idea
00:09:07.02 is that it very might well be wrong.
00:09:09.12 And this had to do with the fact that
00:09:11.13 the person I was working with at the time,
00:09:13.12 Bruce Schneider, published a contemporaneous report
00:09:16.13 showing that the levels of CCK
00:09:18.13 in brain were no different in ob mice versus
00:09:21.27 their lean littermates.
00:09:23.03 And so, we and others wondered whether or not
00:09:25.20 CCK was the defective gene
00:09:27.11 in the ob animals.
00:09:28.28 Well, one of the first things we did
00:09:31.03 at the time was to clone the CCK
00:09:33.14 gene. And the idea was to clone
00:09:35.11 the CCK gene and see where on the
00:09:37.24 chromosome it mapped, whether it mapped
00:09:39.26 near the location of the ob gene.
00:09:42.12 We quickly found that CCK mapped to the
00:09:44.23 distal end of Chromosome 9.
00:09:46.08 This is a map of Chromosome 9 with a variety
00:09:49.00 of genes that map there. The only
00:09:50.26 problem was that the ob gene didn't map
00:09:53.18 to Chromosome 9, it mapped to Chromosome 6.
00:09:56.20 So these data excluded the possibility
00:09:59.24 that CCK was the ob gene.
00:10:01.06 And raised the question, well if it's not
00:10:03.28 CCK, what is it?
00:10:05.13 In the 1980s when we did this work,
00:10:08.08 a new technology was emerging that allowed
00:10:10.20 one to identify defective genes,
00:10:12.10 not based on knowledge of their function,
00:10:14.12 but simply based on detailed knowledge
00:10:17.19 of the chromosomal location of that gene.
00:10:19.27 This methodology was known as positional
00:10:22.17 cloning, and we set out then to identify
00:10:25.00 the ob gene using positional cloning.
00:10:27.21 This required identifying genes in the region
00:10:33.05 of the chromosome where ob was known to map.
00:10:35.19 And one day, on a Friday, we found
00:10:38.00 a gene in the region of ob that was expressed only
00:10:40.06 in fat tissue. This is a Northern blot, it's a way at the time
00:10:43.26 of measuring RNA levels and only
00:10:46.19 fat tissue had an RNA for this gene,
00:10:48.19 which we knew mapped near the ob gene.
00:10:50.19 The next step was to ask, is
00:10:52.17 this gene defective in strains of mice
00:10:55.08 that are genetically obese?
00:10:56.28 And indeed it was.
00:10:58.18 If you look here at lane 2, that's fat tissue
00:11:00.24 from a normal mouse. Lane 3 is fat
00:11:03.05 tissue from an ob mouse of the same
00:11:04.29 strain. That strain fails to make the ob
00:11:08.24 RNA and that's why it's fat.
00:11:10.23 Lane 4 is RNA is fat tissue of a different strain
00:11:13.20 of mouse and lane 5 is RNA from
00:11:16.28 the obese animal from that same strain.
00:11:20.08 In this case, increased levels of RNA are produced
00:11:22.27 and that's because the RNA produces
00:11:25.02 a defective protein. The animal then makes more and more
00:11:28.07 RNA as a means of trying to compensate,
00:11:30.19 unsuccessfully, because the RNA makes a defective
00:11:33.04 protein. Well, the demonstration that
00:11:36.18 this gene was defective in two
00:11:38.05 different obese strains of mice
00:11:39.24 confirmed that we had in fact identified
00:11:42.06 the defective gene, and this was published
00:11:44.09 to some fanfare in 1994 with this image
00:11:48.04 of an obese mouse outweighing two
00:11:50.08 of its sibling littermates.
00:11:52.02 Shortly after identifying the ob gene,
00:11:54.22 subsequent studies revealed, in fact,
00:11:56.28 that the defective gene encoded this hormone
00:11:58.26 leptin. It's the hormone made by fat
00:12:00.26 tissue that regulates appetite by
00:12:03.08 acting on brain centers.
00:12:06.07 One of the key experiments was done by
00:12:09.00 collaborators Jeff Halaas and Ketan Gajiwala and Steve
00:12:11.21 Burley, together we showed that if you inject
00:12:14.09 saline into an ob animal nothing happens,
00:12:16.19 they stay obese. But if you inject leptin
00:12:19.10 made in the laboratory, animals normalize
00:12:21.08 their phenotype. Much the same as O'Rahilly
00:12:23.22 and colleagues later showed for this leptin
00:12:26.09 deficient child.
00:12:27.20 Now leptin mutations are quite rare,
00:12:30.03 there are only a few dozen such mutations
00:12:31.29 in the world, which is characteristic of hormones
00:12:34.07 which are poor targets for mutations.
00:12:36.06 But we now know that perhaps 10-15%
00:12:39.23 of morbid obesity is the result of
00:12:41.16 single gene defects in other genes
00:12:44.05 in the neural circuit on which leptin acts.
00:12:47.05 And so this has provided a great stimulus
00:12:49.09 in research into the causes of obesity,
00:12:52.28 and tells us now that obesity is very often
00:12:56.00 a result of specific genetic defects.
00:12:57.28 I suspect that we'll identify ever more
00:13:00.16 of these defects now, with advances in DNA
00:13:02.19 sequencing and other new technologies.
00:13:05.09 And so I think research in this
00:13:07.05 area has been greatly stimulated by the
00:13:08.27 identification of leptin and the realization
00:13:11.21 that obesity can be the result of genetic defects
00:13:14.11 in a neural circuit that regulates food intake
00:13:17.16 and body weight.

This Talk

Speaker: Jeffrey Friedman

Audience:

General Public
Educators of H. School / Intro Undergrad
Student
Educators of Adv. Undergrad / Grad
Researcher
Educators

Recorded: July 2014

Talk Overview

Obesity is a highly heritable medical condition, with 70-80% of variations in body weight explained by genetic factors. In the 1990s, Jeffrey Friedman and his colleagues were the first to demonstrate the genetic basis for obesity when they identified and cloned leptin, a hormone secreted by fat tissue, as the responsible factor for maintaining normal body weight. Friedman’s research has played a major role in our understanding of human obesity and the hormonal pathway that controls food intake.

Speaker Bio

Jeffrey Friedman

Jeffrey Friedman is a Professor at the Rockefeller University and an investigator of the Howard Hughes Medical Institute. His work on leptin and body weight regulation has been key for our understanding of how genetics control human obesity. Friedman, a member of the National Academy of Sciences, has received numerous awards for his research, including… Continue Reading