Obesity Genetics: Health Consequences of Being Fat

Part 1: The Causes of Obesity: Why Isn’t everybody fat?

00:00:07.14 Hello. I'm Steve O'Rahilly,
00:00:09.16 and I'm a physician scientist at the University of Cambridge.
00:00:11.28 I'm interested in the causes and the consequences
00:00:14.03 of obesity.
00:00:15.24 Obesity is a fascinating field,
00:00:17.22 one indeed which I've wandered into both professionally, and sadly personally,
00:00:21.06 entirely by accident.
00:00:23.11 However, it's a science... it's a field that attracts scientists
00:00:26.16 from a wide variety of disciplines.
00:00:28.11 One can look at it from the point of view of
00:00:30.26 social science and behavioral science.
00:00:32.25 I'm a biomedical scientist,
00:00:35.09 and I'll take an unashamedly biomedical perspective today
00:00:37.28 to ask the question, why isn't everybody fat?
00:00:40.23 What is it that makes some individuals resistant
00:00:43.19 and some susceptible to obesity?
00:00:45.18 And can we use that information
00:00:47.25 to design better therapies for people with obesity?
00:00:52.05 Contrary to what's often thought,
00:00:54.04 obesity is not a new disease.
00:00:57.10 It seems unlikely that the Paleolithic sculptor of these figures
00:01:01.22 was working entirely from imagination.
00:01:05.04 Hippocrates, the great ancient Greek physician,
00:01:08.00 had tremendous trouble managing his obese patients.
00:01:10.22 He said they should eat only once a day,
00:01:13.18 take no baths, sleep on a hard bed,
00:01:15.20 and walk naked as long as possible.
00:01:17.28 Cynics would say we haven't advanced very much further
00:01:20.20 in the management of obesity.
00:01:23.02 Daniel Lambert, the Leicester jailer,
00:01:26.27 was a great 18th century figure
00:01:29.28 and the largest man in Britain of his time.
00:01:31.26 And a similar 18th century physician,
00:01:34.16 Thomas Short,
00:01:37.02 opined that "no age has seen more instances of corpulency than our own."
00:01:40.26 So, obesity is not a new disease; it's always been with us.
00:01:44.10 But it has become more common in recent years,
00:01:47.14 and there must be some explanations for this rapid increase
00:01:50.09 in the secular prevalence of obesity.
00:01:53.09 I think these can be found in relatively simple explanations
00:01:55.21 that most of us would understand.
00:01:57.22 It's never been easier to ingest more calories.
00:02:00.26 They're cheaper, they're more readily available
00:02:03.05 and constantly available,
00:02:05.03 they're put into attractive packages,
00:02:06.19 they're advertised,
00:02:08.11 and they're processed so they're less satiating and easier to eat more of.
00:02:12.16 We're also in an environment where we dec...
00:02:14.24 we expend less calories in both the workplace
00:02:16.24 and in the domestic sphere.
00:02:20.07 Other research has suggested, perhaps,
00:02:22.22 other factors like antibiotics or environmental pollutants,
00:02:24.23 or indeed our antenatal environment.
00:02:26.28 Our mother makes us fat, or our social networks -- our friends --
00:02:29.25 make us fat.
00:02:31.02 These are all tantalizing areas of research,
00:02:32.28 but none have reached, I think,
00:02:35.10 a level of maturity yet to impact on public health policy.
00:02:41.04 The best evidence, I think, for the environmental determinants of obesity
00:02:44.20 is when a population moves from a place
00:02:46.23 where they had a low prevalence of obesity
00:02:48.25 to a place of high prevalence,
00:02:50.27 and where they acquire the prevalence of obesity
00:02:53.21 of the place they've moved to.
00:02:55.05 And that's happened with many migrant populations
00:02:57.14 around the world.
00:02:59.03 A slightly tongue-in-cheek illustration of that is provided...
00:03:01.29 is provided here.
00:03:05.25 So, if we're living in such an obesogenic environment,
00:03:09.20 why isn't everybody fat?
00:03:12.10 I mean, if everybody had the same biology,
00:03:14.10 as I suggest in the top two slides, here,
00:03:16.25 then if we really all have the same biology,
00:03:18.24 perhaps lean people are morally superior?
00:03:20.21 They just make the right choices,
00:03:22.18 and they keep themselves lean,
00:03:24.07 and we should congratulate them,
00:03:26.03 and the rest of us are to be ashamed of the fact
00:03:29.01 that we've not remained [lean].
00:03:30.20 Or they've just been lucky, and they live in environments that tend to promote...
00:03:32.25 promote leanness.
00:03:34.14 Perhaps that's true. But, I have another suggestion for you.
00:03:37.14 Perhaps people have different underlying susceptibilities
00:03:39.28 to being lean or obese.
00:03:41.16 Now, that could either be impervious to environmental factors
00:03:44.00 or it could interact with them.
00:03:47.13 And in the rest of my talk today, I'm probably gonna try and convince you, I hope,
00:03:50.07 that people do have different underlying susceptibilities,
00:03:52.09 but it also interacts with environmental factors.
00:03:59.17 Genetics is extraordinarily important
00:04:01.27 for most variable human traits,
00:04:03.23 and adiposity is no exception.
00:04:06.07 We all accept that height has a very strong heritable trait,
00:04:09.05 but in fact adiposity, or the amount of body fat we carry,
00:04:12.12 is... although not quite as heritable as height is,
00:04:15.00 it's pretty heritable, and more heritable,
00:04:16.24 for example, than IQ.
00:04:18.11 And we have very good data from identical versus non-identical twins,
00:04:21.19 from adoption studies,
00:04:23.11 and even remarkably from identical twins reared apart.
00:04:29.13 Here's a remarkable study done in... by American investigators but in Sweden,
00:04:33.26 taking children who were born in Sweden in the 1950s and '60s,
00:04:37.14 and who... as a matter of policy in that era in Sweden,
00:04:41.02 identical twins, or indeed twins in general,
00:04:44.10 were separated at birth and brought up in different families.
00:04:46.16 And what these investigators did was follow up on their body weights
00:04:49.24 and body compositions later in life
00:04:51.25 to see if the individuals
00:04:55.00 were more similar to the families that brought them up
00:04:56.24 or more similar to the twins
00:04:59.19 that they'd never seen or never interacted with.
00:05:01.28 And rather remarkably, Stunkard, who as a child psychiatrist,
00:05:05.14 and was very surprised at this data...
00:05:07.21 he had to conclude that the genetic influences on body mass index were profound,
00:05:11.15 and they could find no evidence of the childhood environment.
00:05:14.20 In other words, there was no similarity between individuals
00:05:18.09 and the siblings they grew up with,
00:05:20.07 but profound and very strong similarities of body weights and fat
00:05:24.06 with the individuals that they had shared genetic identity with.
00:05:28.07 And here, from a different paper,
00:05:30.03 is just a picture that helps you really get your head around
00:05:33.18 this importance of heritability.
00:05:35.10 On the left-hand side on the bottom
00:05:37.08 are pairs of sisters.
00:05:38.09 And they're sisters who were born on the same day.
00:05:40.17 But they're sisters who were... i.e., they're twins,
00:05:43.22 but they're twins who only share 50% of their genes.
00:05:45.07 And like you and your brothers and sisters,
00:05:47.08 you all come in different shapes and sizes,
00:05:49.02 and so do they.
00:05:50.20 But look on the right-hand side,
00:05:52.05 and look at individuals who share 100% percent of their...
00:05:56.10 of their genome -- and are identical twins... because they're identical twins --
00:06:00.03 and see the remarkable similarities in height, body composition,
00:06:03.00 body shape, body amount of fat.
00:06:05.06 It'd be hard to look at those pictures and say,
00:06:07.00 oh, I don't think heredity is terribly important
00:06:09.12 in determining how much body fat you have.
00:06:14.04 So, how do we determine how much...
00:06:19.05 how is it determined how much adipose tissue one has?
00:06:23.03 And indeed, the causes of obesity are actually rather simple.
00:06:26.01 We store energy largely as fat,
00:06:29.21 and our energy stored is equal to our energy intake
00:06:33.04 minus our energy expended over a period of time.
00:06:35.29 But of course, we don't necessarily
00:06:39.24 have to store all that excess energy as fat.
00:06:42.10 We can store it as non-fat tissue.
00:06:44.20 I've often had a dream that I could go out for a big curry in the evening,
00:06:47.24 and instead of putting on weight on my waistline,
00:06:50.07 I could put it into a vigorous beard growth
00:06:52.22 that I could cut off in the morning.
00:06:54.06 But sadly, my body is not designed that way.
00:06:56.00 Our body is designed to store fat in fat tissue.
00:06:58.24 It's the professional storage tissue
00:07:01.20 that's there to be able to store fat efficiently,
00:07:03.16 because adipose tissue triglyceride is a very efficient store
00:07:07.03 with very little water,
00:07:08.25 so we can store it at the lowest possible weight,
00:07:11.01 and store it so that they can be released slowly
00:07:15.11 when we need it, when we...
00:07:17.11 in evolutionary terms,
00:07:19.19 when we went through periods of less availability of energy.
00:07:23.03 So, we get through a remarkable amount of food
00:07:28.00 in our lifetimes.
00:07:29.17 And we don't get through the same amount every day.
00:07:31.14 We have the oscillations throughout the day of availability
00:07:34.02 and what we do and our physical activity.
00:07:37.11 And yet we don't tend to oscillate in weight
00:07:41.12 between supermodels and opera divas.
00:07:44.04 We tend to stay within relatively stable parameters,
00:07:48.06 most of us.
00:07:50.07 And so that implies that there must be
00:07:53.06 some form of regulation going on.
00:07:56.24 And the first clues for that came from
00:07:59.20 experiments in rats done by
00:08:02.09 both Gordon Kennedy in Britain and workers in the United States
00:08:04.20 in the 1940s and '50s.
00:08:06.12 And they did very simple experiments.
00:08:08.09 So, if you take a rat... a rat basically grows constantly.
00:08:10.19 It doesn't really stop growing.
00:08:12.09 So, if you see a big rat, it's an old rat.
00:08:14.08 And if you take a rat and deprive it of
00:08:18.25 50% of its calories, it will lose weight.
00:08:20.20 If you then put it back in its original cage with the...
00:08:23.07 with its abundant food, it rapidly eats
00:08:28.11 and gets back to exactly where it would have been on the trajectory,
00:08:30.28 if you'd let it go there in the first place.
00:08:32.28 So, it knows where it wants to be
00:08:34.28 in terms of its amount of energy storage.
00:08:36.15 And these are really the first, very simple but clear, experiments
00:08:40.04 that there was something controlling the amount of energy store in the...
00:08:43.26 in the mammalian body.
00:08:45.22 What organ in the body do we think is sensing those?
00:08:49.03 What... what organ, if it went wrong, would those energy storing mechanisms...
00:08:55.04 you know, where would...
00:08:57.11 where would that impact be?
00:08:58.29 Well, we learned that first, I think, from German physicians in the 19th century,
00:09:02.26 who had patients who developed tumors in the hypothalamus.
00:09:06.13 And those patients went from being lean to being obese to be overeating --
00:09:10.29 so-called hyperphagic.
00:09:12.18 And when they died, they discovered that they had tumors
00:09:15.15 in this specific area of the brain, the hypothalamus,
00:09:18.12 the first pointer to the fact that this was the area of our bodies
00:09:21.04 which was concerned with the long-term regulation
00:09:23.24 of our body weight.
00:09:25.28 And to take that science further,
00:09:27.16 scientists in the early part of the last century
00:09:30.14 tried to create lesions in this tiny area of the brain,
00:09:33.28 the hypothalamus.
00:09:35.12 And by... if you... if you lesion the middle bit,
00:09:37.18 the so-called medial hypothalamus,
00:09:39.10 of a rat or mouse you get an animal that eats a huge amount
00:09:42.02 and becomes very fat.
00:09:43.29 If you move the needles micrometers to the side,
00:09:47.10 and lesion the lateral parts of the hypothalamus,
00:09:49.21 you can create a perfectly healthy animal that will drink and interact and...
00:09:52.17 but will never eat again.
00:09:54.24 It will never initiate an eating behavior.
00:09:56.15 So, this tiny bit of the brain
00:09:58.27 is crucially important for the control of eating behavior.
00:10:04.15 I think the crucial first experiment in the modern obesity era
00:10:08.02 was really done by... done by Hervey,
00:10:11.09 a scientist here in Cambridge, in a small lab in the center of town,
00:10:15.18 and he did a so-called parabiosis experiment.
00:10:18.10 He connected the circulations of young rodents
00:10:21.29 so that hormones could pass through from one to the other.
00:10:25.22 And then, in one of the rodents,
00:10:28.06 he lesioned the hypothalamus in order to make...
00:10:30.11 in order to make it overeat and become obese.
00:10:33.00 And he wanted to know what would happen to the other animal.
00:10:35.28 And indeed, what happened to the other animal is it stopped eating,
00:10:39.11 or lost interest in eating,
00:10:40.28 and lost a huge amount of weight.
00:10:42.16 And that led him to cont... consider...
00:10:44.11 led him to conclude that there must be a circulating factor,
00:10:47.01 which is present in excess in obesity,
00:10:50.16 which is suppressing food intake in an otherwise healthy animal.
00:10:55.14 This... this technique was then
00:10:59.03 applied to genetically obese forms of animals
00:11:01.14 in the Jackson Laboratories at Bar Harbor, Maine,
00:11:05.24 where... which... which was an animal which was used to keep colonies of
00:11:10.03 various spontaneous mutants in mice.
00:11:11.29 And what Coleman showed is by doing this cross-circulation experiment,
00:11:14.25 one of those very obese forms of mice
00:11:17.05 could effectively be cured by whatever was being produced
00:11:20.11 by a normal mouse passing across the circulation
00:11:24.08 and curing the ob/ob mouse.
00:11:26.13 It took the power of modern molecular genetics,
00:11:29.27 and another further 20 years,
00:11:31.28 for the discovery of what was causing that obesity
00:11:34.13 in the ob/ob mouse.
00:11:35.28 And that was the lack of a circulating hormone called leptin.
00:11:39.12 There was a genetic mutation which blocked the action of leptin.
00:11:43.07 And this caused this mouse to be more than twice the weight of its siblings.
00:11:47.17 Leptin, remarkably, was produced by...
00:11:52.08 only by adipose tissue.
00:11:54.02 It's made in fat cells.
00:11:55.22 It's made... the bigger a fat cell becomes,
00:11:57.15 the more leptin it makes.
00:11:59.03 Leptin goes and acts in...
00:12:01.14 predominantly in the brain,
00:12:03.26 and indeed, predominantly in the hypothalamus,
00:12:05.14 where it decreases food intake,
00:12:07.03 increases thermogenesis,
00:12:08.22 and decreases... sorry, increases physical activity.
00:12:13.09 So, remarkably, this was the first example, really,
00:12:17.08 of understanding that the brain had a signal
00:12:19.28 that was given to it by the body
00:12:22.01 to keep it informed of its long-term state
00:12:24.18 of nutritional storage.
00:12:26.21 The last 20 years has seen a huge acceleration
00:12:30.27 in the pace of our understanding of signals
00:12:33.21 that go to the brain
00:12:35.09 and keep it informed about nutrients.
00:12:37.00 Leptin is a long-term signal.
00:12:38.25 It provides long-term information
00:12:41.01 about how much energy we have stored.
00:12:43.10 On the other hand,
00:12:45.14 our gut is full of endocrine cells,
00:12:47.04 full of hormone-producing cells,
00:12:49.03 and they sense how much we eat in an individual meal
00:12:52.06 and, indeed, help sense what the constituents of those meals are,
00:12:55.25 in terms of protein, fat, carbohydrate.
00:12:58.12 And that complex of signals coming through
00:13:01.20 really gives us the minute-to-minute information
00:13:05.19 about what we've been eating,
00:13:07.16 and bringing that information to the brain.
00:13:09.14 In work we did ourselves, in Cambridge,
00:13:11.26 with our colleagues Frank Reimann and Fiona Gribble,
00:13:13.29 we added, more recently, to that list of hormones
00:13:16.23 through the peptide insulin-like 5.
00:13:20.21 These discoveries are already impacting on clinical practice.
00:13:25.03 One such hormone, GLP-1 (glucagon-like peptide 1),
00:13:28.11 is now an effective anti-obesity therapeutic,
00:13:30.23 one of the first forms of this so-called Liraglutide.
00:13:34.14 Here, you see in this slide a dramatic effect on body weight,
00:13:38.09 reducing... 10% reductions in body weight
00:13:40.27 over a year study in individuals given this analog of GLP-1.
00:13:44.22 And newer analogs of this are proving even more powerful,
00:13:48.15 and indeed there are now oral analogues in development,
00:13:51.22 which should be much more wi...
00:13:54.26 gain much more widespread use as effective anti-obesity agents.
00:14:00.09 What about the long-term storage signals?
00:14:02.28 I've only shown you data so far in mice.
00:14:05.02 Is this a mouse-specific phenomenon?
00:14:07.07 Well, that's where my lab came in.
00:14:08.24 And back more than 20 years ago now,
00:14:13.28 we discovered the first humans who had disruptions in these pathways,
00:14:19.23 disruptions in the pathways of long-term energy...
00:14:23.03 long-term signaling from...
00:14:25.21 in the leptin system, including children, on the right, who lack leptin,
00:14:30.09 and an individual on the left who lacks a signal downstream of leptin
00:14:33.27 within the... within the brain.
00:14:35.29 And those first discoveries, those first two families we studied,
00:14:39.03 really opened up an era of great excitement for us,
00:14:42.19 where we decided to focus on the study of severely obese children,
00:14:46.05 and see if we could find more of these children,
00:14:49.01 and whether they all had these lesions or other types of defects.
00:14:53.20 And I was joined around that time by my wonderful colleagues,
00:14:56.12 who are still in Cambridge, Sadaf Farooqi, Giles Yeo, Tony Coll,
00:14:59.12 and we had an exciting journey
00:15:02.23 discovering these new genetic conditions resulting in obesity.
00:15:05.24 We, and indeed other groups around the world, made much...
00:15:10.08 many advances in the early 2000s in discovering such conditions.
00:15:16.19 The key messages really are two-fold.
00:15:18.24 We didn't know where these obesity genes would be acting.
00:15:22.10 But when we discovered them,
00:15:24.16 we found that they were largely expressed in the brain.
00:15:26.28 And the second thing we discovered is that
00:15:30.00 when we studied the children who carry these genetic mutations,
00:15:34.16 they weren't predominantly becoming obese
00:15:38.18 because they weren't burning off calories.
00:15:40.11 They were predominantly becoming obese because they ate too much.
00:15:42.27 They had a profound appetite drive.
00:15:44.22 They were not satiated by the same amount of food
00:15:46.17 as their wild type siblings,
00:15:49.08 the siblings carrying the normal genes.
00:15:50.23 Here in black, for example, is the food intake per kilogram of lean mass
00:15:55.19 in... in normal, control children
00:15:58.19 and in matched children of... similar degrees...
00:16:02.14 similar ethnicities and similar ages,
00:16:04.27 who have defects in the leptin pathway.
00:16:07.00 And these children with defects just eat hugely more food at a test meal
00:16:11.08 than those children who have wild type genes.
00:16:14.19 So, this has caused, I think... it's...
00:16:18.22 it's been a hard concept to get across,
00:16:20.24 because these are genetic conditions,
00:16:22.26 but they're genetic conditions not so much affecting metabolism
00:16:24.22 but affecting a behavior.
00:16:26.19 And we often, as human beings,
00:16:28.26 are uncomfortable about the idea that our behavior is not entirely under our own control.
00:16:32.24 So, these are primary, single-gene disorders
00:16:35.24 that cause their problem by influencing
00:16:38.20 how much we eat and how much we want to eat.
00:16:42.18 Over the last 10 years, the leadership in this area
00:16:45.06 has been taken over and handed over to Sadaf Farooqi,
00:16:48.09 who has worked closely with colleague Ines Barroso.
00:16:51.05 And she and others around the world
00:16:53.15 have continued to discover genes -- more genes --
00:16:56.19 the disruption of which causes... cause obesity.
00:17:01.21 One of the criticisms we had when we first started to present this
00:17:05.00 was that many people who were skeptical about the biology of obesity
00:17:08.01 said, well, this may be relevant for these rare children,
00:17:12.03 but is it relevant at all for the common obesity around the world,
00:17:15.20 the variation in the amount of fat that we have
00:17:19.00 in a... in a... you know, if you take a crowded bus or a theater...
00:17:21.17 you know, people ranging from thin to fat...
00:17:23.24 how relevant is genetics in those circumstances?
00:17:26.18 Well, over the last decade or more,
00:17:28.17 we've started to be able to answer that question
00:17:31.00 through the study of large volunteer populations,
00:17:33.08 hundreds and, indeed, hundreds of thousands of people,
00:17:35.25 and now the power to be able to interrogate
00:17:38.25 the broader genome for all its variation,
00:17:41.05 or at least the majority of its variation.
00:17:44.11 Here's one early example, I think a rather beautiful one.
00:17:47.14 It's been... it's been only strengthened by subsequent work.
00:17:51.05 And... and in this paper,
00:17:54.11 over 300,000 people with information on their body mass index,
00:17:57.09 their amount of adiposity,
00:17:59.07 have been... have been... have been studied.
00:18:01.22 And 97 variants around the genome have been associated...
00:18:06.05 unequivocally, with [low] high P-values, associated with BMI.
00:18:10.04 Now, those genes sit in certain parts of the genome.
00:18:12.19 They influence gene expression.
00:18:14.02 They influence gene expression in certain tissues.
00:18:16.18 And that can be calculated.
00:18:18.12 So, what we have on the x axis of this graph is a range of tissues.
00:18:21.29 And... and we're gonna show you in a moment
00:18:24.14 where those genetic SNPs are mostly affecting gene expression.
00:18:28.07 Obesity could, you imagine, might be due to excess digestion of fat
00:18:31.26 or hormonal problems --
00:18:33.25 that could be predominant in the digestive or endocrine system.
00:18:36.04 But our single-gene disorders suggested the brain was very important.
00:18:39.20 And you won't be surprised, therefore,
00:18:41.24 to see that the nervous system is the place
00:18:44.05 where this genetic variation is having its most profound effect.
00:18:49.00 And that takes me to a lovely study of Jane Wardle,
00:18:51.10 a collaborator and old friend
00:18:54.15 who very tragically died far too young a couple of years ago.
00:18:56.15 And Jane was a clinical psychologist,
00:18:58.10 and she developed beautiful questionnaires
00:19:00.22 that she would give to young children and families of you...
00:19:03.23 parents of young children that effectively predicted
00:19:06.09 the development of obesity based on their responsiveness to food cues
00:19:09.29 or their responsive to satiety cues.
00:19:12.07 And these were very strongly predictive of their later development of obesity.
00:19:17.13 And with the development of modern genetics,
00:19:19.19 Jane and her colleagues were able to layer on studies of genetic variation.
00:19:23.16 And in this very nice study,
00:19:25.27 she showed here that the genetic variation
00:19:28.28 that results in decreased satiety responsiveness
00:19:31.02 really maps on beautifully to the genetic variation
00:19:33.13 that maps onto adiposity.
00:19:35.29 So, really making almost for the first time the link between genes,
00:19:39.07 a behavior (responsiveness to satiety cues),
00:19:42.05 and finally the amount of adipose tissue one has.
00:19:45.25 And adapting a further slide of Jane's,
00:19:48.28 I'll just give you this slide to end this particular part of the talk.
00:19:53.08 Because people often say, well, you know, it must be all environment,
00:19:57.22 because when there's a famine, you know, nobody gets fat.
00:20:00.15 And it's true, we cannot get obese if you're in a famine.
00:20:03.02 But, of course, as soon as you get into areas of even adequate nutrition,
00:20:05.27 there will be some individuals who are going to be
00:20:09.10 highly susceptible to obesity and will develop obesity.
00:20:11.10 And as we are now, in an abundant or super-abundant climate,
00:20:14.07 even those with average genetic susceptibilities are develop...
00:20:17.05 are becoming obese.
00:20:19.13 And those with strong susceptibilities
00:20:21.17 find it extremely difficult to avoid obesity.
00:20:23.29 And what the precise work we've done
00:20:26.29 -- defining the nature of the genes --
00:20:29.04 suggests is that those genetic variants
00:20:32.01 are affecting appetite genes predominantly.
00:20:33.16 And that should, I think, influence our public policy
00:20:36.03 in terms of making the environment less obesogenic and less...
00:20:40.12 providing continual stimulus to food intake
00:20:43.19 throughout our daily lives.
00:20:47.07 What about therapy?
00:20:49.23 Well, we had an enormous privilege and pleasure
00:20:52.03 in discovering that the kids we...
00:20:55.03 in whom we found congenital leptin deficiency
00:20:57.24 could be wonderfully and quickly returned totally to normal
00:21:01.03 by daily injections of the peptide leptin.
00:21:04.05 You see here on the left-hand side an example of a very obese child
00:21:07.28 returning to normal.
00:21:09.12 We can do this much quicker now and much more aggressively.
00:21:11.16 We can get children back to normal weight within a few months,
00:21:13.24 six months maybe.
00:21:16.15 So, on the right,
00:21:20.08 I think is one of the most elegant experiments that I was involved in with my colleagues,
00:21:23.13 Sadaf Farooqi and Paul Fletcher and Ed Bullmore and others.
00:21:26.07 And that's when we were able to study some adolescent
00:21:30.11 congenitally leptin-deficient children
00:21:32.15 who'd never seen leptin.
00:21:34.05 So, you show them pictures of food and you put them in an MRI scanner
00:21:37.02 to look at areas of brain activation.
00:21:39.02 And if you show them pictures of non-food, not very much happens.
00:21:43.04 If you show them pictures of food,
00:21:44.19 whether it's a burger or broccoli,
00:21:46.15 the areas of the brain that are concerned with addiction and reward
00:21:50.19 light up like a beacon.
00:21:52.08 So, huge activations compared to normal individuals
00:21:55.05 in those areas of the brain,
00:21:56.27 irrespective of the type of foodstuff.
00:21:59.01 But within three days of giving them leptin injections
00:22:01.29 -- and remember, they haven't lost any weight by this stage;
00:22:05.07 they're completely the same weight as they were before --
00:22:07.15 you can see from the black and the white bars, there,
00:22:09.24 that activation disappears completely.
00:22:11.13 So, here we have a little molecule coming from our fat cells,
00:22:13.23 going all the way to our brain,
00:22:15.24 and having profound influences on how our brain is thinking
00:22:19.00 and perceiving even visual images.
00:22:21.24 So, all of you listening, here,
00:22:24.04 this is happening in you right now.
00:22:25.24 Because everybody who has no leptin
00:22:28.00 is essentially a food-seeking missile.
00:22:30.01 The absence of... abs... of leptin turns your brain
00:22:33.20 entirely into the... thinking about food.
00:22:36.20 So, we think that maybe we're...
00:22:39.04 we're very unconscious of our leptin action.
00:22:40.20 But believe me, if you didn't have any,
00:22:42.21 you wouldn't really be watching this.
00:22:45.07 You'd be... you'd be at your refrigerator finding... finding food.
00:22:51.03 Why then is leptin not a blockbuster drug for obesity?
00:22:55.10 It's phenomenally effective in the kids with congenital leptin deficiency
00:22:57.26 and, indeed, in children with congenital lipodystrophy,
00:23:00.10 who have no adipose tissue.
00:23:02.23 That's perhaps, I think,
00:23:04.28 down to its dose-response curve.
00:23:06.07 A lot of hormones act a bit like model 1 here:
00:23:08.07 the more hormone you give,
00:23:10.05 the more effect you have.
00:23:12.02 But with leptin, probably because of its evolutionary origins
00:23:15.02 as a signal of starvation rather than a sig...
00:23:18.10 necessarily a signal of plenty,
00:23:20.16 when your leptin drops, it's a bit like
00:23:23.28 the dog that didn't bark in the Sherlock Holmes
00:23:27.18 "the dog that didn't bark in the night."
00:23:29.09 It does its most important signaling in its absence
00:23:32.03 rather than its presence.
00:23:33.20 So, the drop of leptin down to the bottom of the scale
00:23:36.08 really sets off a screaming signal in the brain.
00:23:38.22 And when you reverse that, you get a big effect.
00:23:40.16 You go from no leptin to some leptin,
00:23:42.20 and you get a fantastic effect.
00:23:44.07 But as soon as you're into the normal range,
00:23:45.24 it flattens off greatly.
00:23:47.23 So, treating regular obese people with leptin
00:23:50.20 hasn't worked terribly well,
00:23:52.12 and it has not become a blockbuster drug.
00:23:54.23 But I think there is some hope for an extension of leptin agonism
00:23:58.01 as a therapeutic.
00:23:59.16 Partly, this comes from work we did
00:24:02.16 on data from an Amgen clinical trial, which they...
00:24:06.05 it was the first clinical trial in regular obesity,
00:24:08.18 and they did not think that it was commercially viable
00:24:12.00 given the effects overall.
00:24:13.18 But if you look at the data in a post hoc way,
00:24:15.11 and you look at the very bottom bar, here...
00:24:17.21 are individuals who were at the lowest level of starting leptin.
00:24:21.15 Individuals who had leptin levels that were very low for their degree of obesity to start with
00:24:28.02 had a much bigger impact than individuals who had moder...
00:24:30.05 moderate or high levels of leptin.
00:24:32.14 And do such people...
00:24:33.28 are such people around in... in general populations?
00:24:37.04 Here's some data locally, from my colleague Nick Wareham and his Fenland study
00:24:42.19 of over 10,000 people,
00:24:45.00 and leptin measured in them all.
00:24:46.14 You can see out there... beyond the red bar are obese people.
00:24:49.01 And in that obese group,
00:24:50.20 there are certainly subsets of small numbers
00:24:53.00 with really profoundly low leptin levels.
00:24:56.03 And if those individuals could be targeted for leptin therapy,
00:24:58.19 that might mean that leptin
00:25:01.13 is a much broader therapeutic compound than it currently is.
00:25:07.06 The field of obesity therapeutics based on this system is gathering pace.
00:25:12.03 Here's a drug: Setmelanotide, a melanocortin-4 receptor agonist.
00:25:16.27 That is essentially the next message along from leptin action within the brain.
00:25:21.08 And this is given to an individual who lacks... or indiv...
00:25:26.12 two individuals who lack that message,
00:25:28.24 who are extremely obese,
00:25:30.11 as shown on the left, the top two graph...
00:25:32.17 patient graphs on the left, showing their weight.
00:25:34.19 And here on the ri... on the right are... in the...
00:25:37.13 in the solid line is the body weight in response to
00:25:41.04 using daily injections of this artificial ligand.
00:25:43.05 And in both cases, the weight goes down phenomenally.
00:25:45.17 There's a cessation of weight loss when individuals
00:25:48.26 have stopped therapy for a short period for a different reason.
00:25:52.00 And the weight went back up.
00:25:54.08 Their appetite scores are shown in the blocks.
00:25:57.11 And you can see that this is having a really profound effect.
00:26:00.22 So, Metreleptin is only useful at the moment
00:26:03.04 in a very small number of individuals.
00:26:05.03 This agent is being tested more widely in broader obesity.
00:26:08.04 And there are other agents currently being developed
00:26:11.24 around the area of leptin action and leptin resistance.
00:26:15.01 So, much going on in the field at the moment.
00:26:18.27 So, in the final part of my talk,
00:26:21.20 I'll ask about the biology of obesity
00:26:24.08 and its relevance to obesity as a public health problem.
00:26:27.19 I mean, is obesity, for example, like smoking?
00:26:30.11 We've done very well on smoking.
00:26:33.14 We've done well on smoking by individual and population behavior changes
00:26:39.09 through a range of techniques:
00:26:41.15 informing, facilitating, incentivizing,
00:26:43.08 even coercing individuals with smoking.
00:26:45.04 And we've made a big impact.
00:26:46.22 But the difficulty with obesity is that food is the...
00:26:49.16 is the issue, not cigarettes,
00:26:51.13 and we all have to eat.
00:26:53.18 So, it's not as simple as simply stopping a single behavior.
00:26:56.00 I think a more useful analogy is that of hypertension.
00:27:01.18 When I was a young doctor,
00:27:03.18 the wards I used to walk were full of patients
00:27:06.03 with the end-stage consequences of uncontrolled and undetected hypertension.
00:27:10.12 And now, as a doctor, I rarely see that in the hospital wards.
00:27:13.11 It's a problem that effectively has been...
00:27:16.07 if not... if not cured... but hugely ameliorated.
00:27:18.23 So, how did we do that over a time peri...
00:27:22.11 a relatively short time period?
00:27:24.11 Well, let's look at hypertension
00:27:27.01 nad let's compare it with obesity.
00:27:28.17 Hypertension is simply the high end of a blood pressure distribution
00:27:32.16 and obesity the high end of an adiposity distribution.
00:27:35.04 And we choose an arbitrary cutoff point at a...
00:27:38.00 at a point at which we know you get adverse health benefits
00:27:40.20 to the right of that... of that curve...
00:27:43.28 adverse health disbenefits to the right of that curve.
00:27:48.05 But if we look at what we've done with hypertension,
00:27:51.09 we can take a historical perspective.
00:27:53.01 We can look at the 1940s,
00:27:56.25 or even before the 1940s,
00:27:58.07 and the only thing you could really do for someone with severe hypertension
00:28:01.27 was give them a low salt diet,
00:28:03.14 the so-called rice diet.
00:28:05.02 Intolerable beyond a few weeks.
00:28:06.17 People really hated it.
00:28:08.13 It did bring their blood pressures down, but it didn't...
00:28:10.07 they really couldn't tolerate it.
00:28:11.19 Then, in the 1940s,
00:28:13.13 surgical approaches were taken.
00:28:15.18 Cutting the sympathetic chain in the neck,
00:28:17.25 yes, could be effective, but caused severe postural hypotension.
00:28:20.06 Some people could never stand up again.
00:28:22.18 Then, in the 1950s,
00:28:25.26 drugs were developed with severe side effects.
00:28:29.14 They did have some efficacy, but they were very toxic.
00:28:31.03 And gradually, some better drugs started to be developed.
00:28:33.11 And then, in the '70s and '80s,
00:28:35.10 we began to understand more about the physiology of blood pressure control,
00:28:38.15 the role of the kidney,
00:28:40.18 the role of the renin-angiotensin system.
00:28:41.12 And now, from the 1970s onwards,
00:28:43.26 we have a panoply of different drug agents,
00:28:46.24 all targeted largely on disease mechanism,
00:28:48.24 and now available as generic and cheap agents.
00:28:52.26 And really, effectively, there's almost nobody
00:28:55.10 whose blood pressure cannot be controlled
00:28:57.26 by an effective combination of those drugs.
00:28:59.17 So, is there an analogy with obesity?
00:29:01.17 I think there is.
00:29:02.29 We can, like the low salt diet,
00:29:04.10 demand that people take extremely demanding diets and exercise.
00:29:06.22 And many people can for short periods of time,
00:29:09.02 but it becomes very difficult to sustain that over long periods of time.
00:29:13.20 We can undertake bariatric surgery.
00:29:15.21 Probably underused in this country,
00:29:17.15 it is very effective in severe cases.
00:29:21.01 But nonetheless, not really applicable across the board.
00:29:24.05 Then we went through a phase of developing drugs which either didn't work
00:29:26.28 or, if they did work, were very toxic.
00:29:29.19 So, that was a very bad phase of anti-obesity drug development.
00:29:33.09 But now, a bit like hypertension,
00:29:36.01 we're beginning to get to agents which may start to be used more widely,
00:29:40.03 and which have a reasonable efficacy and safety profile.
00:29:45.27 So, we need, as we did with high blood pressure...
00:29:50.05 for obesity, we need a multidisciplinary approach... approach.
00:29:51.29 For high blood pressure, we got success
00:29:54.00 through a combination of public health policies,
00:29:57.06 including salt intake policies,
00:30:00.26 and screening and finding individuals with high blood pressure,
00:30:02.29 and the combination of drugs to treat them properly.
00:30:05.29 And they're now generic, cheap,
00:30:07.24 and can be effectively combined.
00:30:09.17 I think, similarly, for obesity
00:30:11.18 we're gonna need strong public health measures
00:30:14.01 focused on prevention,
00:30:15.09 and we're gonna need the selective use of cheap, safe...
00:30:18.02 effective and safe medications,
00:30:20.10 probably in combination.
00:30:21.23 But to develop the latter, we're going to need a much deeper understanding
00:30:26.16 of the molecular physiology of human energy balance.
00:30:28.16 And I hope I've given you some flavor
00:30:30.24 of the advances we've made in that area today.
00:30:33.26 I'd like to finish by thanking colleagues and collaborators,
00:30:37.09 referring physicians,
00:30:38.23 our funders,
00:30:40.14 but particularly the patients, participants, and families,
00:30:42.11 without whom we would not have had a research program in this area.
00:30:44.23 And thank you for your attention.

Part 2: Why Does Obesity Lead to Adverse Health Outcomes?

00:00:07.28 Hello. I'm Steve O'Rahilly.
00:00:09.28 I'm from the University of Cambridge.
00:00:11.10 I'm interested in what makes us fat,
00:00:13.12 and when we get fat, why do we get sick?
00:00:15.09 And in today's talk, I'm gonna talk about why obesity
00:00:18.02 leads to its adverse health outcomes.
00:00:21.06 Obesity is really the effect...
00:00:23.04 the end effect of an excess of energy intake
00:00:25.14 over energy expenditure.
00:00:26.28 This leads to an expanded mass of triglycerides
00:00:29.28 in our fat cells, in our adipocytes,
00:00:31.21 and that's how we define obesity.
00:00:33.25 But really, we're worried about obesity
00:00:35.26 not because of the cosmetic effect of this
00:00:37.29 but because of the health effects.
00:00:39.17 And I think it's useful to group those into three.
00:00:43.01 Firstly, there's mechanical and gravitational effects, if you like:
00:00:46.15 the weight influencing the fact that we increase
00:00:51.08 the risk of osteoarthritis of the knees,
00:00:53.11 the increased intra-abdominal pressure leading to reflux esophagitis,
00:00:55.18 the narrowed airway leading to sleep apnea.
00:00:58.03 So, there's clearly a direct link there
00:01:00.26 between the expanded mass of triglyceride in fat cells
00:01:03.27 and the adverse effects.
00:01:06.14 But when it comes to cancers and metabolic diseases,
00:01:09.00 it's not quite so clear why
00:01:13.03 having an expanded mass of triglyceride in fat cells leads to those.
00:01:15.04 In fact, it opens the question of, does it?
00:01:17.02 Is the obesity just a marker?
00:01:19.28 And is it something about the chronic energy intake over energy expenditure
00:01:24.04 that's directly leading to these cancers and metabolic diseases?
00:01:27.28 The way we've tried to address this question over the years
00:01:31.00 is to find one key phenomenon
00:01:33.14 very closely associated with obesity
00:01:35.20 and predisposing to metabolic disease
00:01:38.07 and, indeed, cancer.
00:01:39.09 And that's the biochemical marker of insulin resistance.
00:01:42.29 Now, as individuals get fatter,
00:01:45.15 they tend to need more insulin to control blood glucose
00:01:49.11 than they did when they were slimmer.
00:01:51.11 So, here's a graphical representation of that.
00:01:54.26 And you can see that the amount of insulin
00:01:57.05 actually varies enormously across the population.
00:02:00.13 There are some people who are obese
00:02:02.19 who don't become particularly insulin resistant,
00:02:04.12 but some do become severely insulin resistant
00:02:06.03 and require a lot of insulin to maintain normal...
00:02:08.26 normal blood glucose.
00:02:11.29 Insulin resistance comes with a lot of additional baggage.
00:02:15.05 Gerald Reaven in the United States, some 20 years ago or more,
00:02:18.19 pointed out that individuals who are insulin-resistant
00:02:21.14 have high cardiovascular risk.
00:02:23.14 They have abnormal circulating blood lipids.
00:02:25.28 They have abnormal clotting factors.
00:02:27.28 They have fatty liver.
00:02:29.16 They're more prone to a range of disorders,
00:02:31.16 not just simply an increased risk of insulin resistance
00:02:34.08 and type 2 diabetes.
00:02:37.15 So, a key question is,
00:02:41.05 how do we get from obesity to insulin resistance?
00:02:43.14 Because insulin, in the whole body,
00:02:46.18 affects predominantly the muscle and the liver.
00:02:48.24 The adipose tissue itself doesn't really concern itself
00:02:52.12 with taking up too much glucose
00:02:54.19 compared to those major glucose-controlling organs,
00:02:57.00 liver and muscle.
00:02:58.14 So, how do we get from sustained positive energy balance
00:03:00.23 to insulin resistance in liver and muscle?
00:03:04.07 If you were to ask a hundred diabetes researchers these days,
00:03:07.06 or a hundred practicing diabetologists,
00:03:08.23 they'd probably say,
00:03:10.23 well, we think we know that now.
00:03:12.06 We think it's because the fat cell becomes large,
00:03:14.10 the adipose tissue depot becomes inflamed,
00:03:17.02 and the fat cell produces a range of circulating or paracrine factors
00:03:20.27 which somehow influence insulin and glucose handling
00:03:25.16 in liver and muscle.
00:03:27.05 And there's abundant evidence from mouse experiments
00:03:30.01 that this is true,
00:03:31.16 but the support of evidence for humans,
00:03:33.05 as I'll come to later, is somewhat less secure.
00:03:35.16 There's another and somewhat older idea about how the...
00:03:40.05 how we might translate this sustained energy balance
00:03:43.00 into insulin resistance.
00:03:44.08 And that's one where... I some...
00:03:46.29 I sometimes say it's where your fat cell
00:03:49.09 is not your enemy; your fat cell is your friend.
00:03:51.16 Your fat cell is by far the safest place
00:03:54.01 to keep positive energy...
00:03:56.09 energy balance and keep calories.
00:03:57.27 And it's only when you start reaching
00:04:00.16 the limits of safe fat cells...
00:04:02.18 fat storage of triglycerides,
00:04:04.11 and those nutrients start to go to non-professional storage tissues
00:04:07.08 such as liver and muscle,
00:04:08.25 then it's the ectopic lipid and the ectopic nutrients
00:04:11.14 that are really causing the mischief
00:04:13.17 and causing insulin resistance and defective glucose handling
00:04:16.16 in these tissues.
00:04:20.22 One of the reasons we've got to the notion
00:04:23.18 that this is an interesting idea
00:04:25.14 is partly the fact that we've been studying patients with severe insulin resistance
00:04:29.09 for over 25 years.
00:04:30.21 And over those years, we have found...
00:04:32.11 we've looked for people who have extremely high levels of circulating insulin,
00:04:35.10 and we've looked, genetically,
00:04:37.12 to find signaling defects,
00:04:40.08 defects in how insulin works in the cell
00:04:42.10 to control blood glucose.
00:04:44.02 And we found a number of individuals
00:04:46.20 and a number of genetic defects as...
00:04:48.12 as sort of illustrated in this slide here.
00:04:50.29 But I think one of the most important things we've learned
00:04:54.09 is from taking those individuals
00:04:55.29 and then measuring the variety of physiological variables
00:05:00.17 that we find in those people with defective insulin signaling,
00:05:04.11 and then compare them to people with the typical metabolic syndrome.
00:05:08.03 So, in the top two rows, you see that in
00:05:11.23 both our individuals with signaling defects and typical metabolic syndrome,
00:05:14.23 insulin levels are high, diabetes risk is increased.
00:05:18.01 But below that, we start seeing,
00:05:21.00 really, quite marked divergences.
00:05:22.09 When you have a defect in insulin signaling,
00:05:24.07 you actually have no abnormalities, often,
00:05:27.28 in triglycerides or HDL.
00:05:29.15 You very often have no abnormalities in liver fat.
00:05:32.08 And you often, indeed, have an increased serum adiponectin.
00:05:34.29 These all diverge markedly from individuals with,
00:05:37.26 if you like, common, or garden, metabolic syndrome or insulin resistance.
00:05:41.06 But there was one set of conditions
00:05:45.03 we've studied over the last a couple of decades
00:05:47.04 where we really do see a complete metabolic phenocopy,
00:05:51.21 and that's quite individuals with lipodystrophy.
00:05:53.29 These are individuals who are insulin resistant
00:05:56.11 because they either cannot make fat cells
00:05:59.00 or they cannot keep triglycerides within fat cells,
00:06:03.20 and they develop as pictured here:
00:06:06.13 an absence of body fat, fats elsewhere in the... in the body,
00:06:09.12 as shown under the skin of the feet or in the... in the...
00:06:12.07 in the eye circulation.
00:06:13.29 And with my wonderful colleague, David Savage,
00:06:17.04 and others over the last few years,
00:06:19.00 we've discovered many of the genes, in collaboration with others,
00:06:22.27 and indeed, other groups around the world have discovered other genes.
00:06:26.15 And so, we now understand a lot more
00:06:29.03 about the genetic architecture of lipodystrophy.
00:06:32.16 Here's one example, I think, which is particularly illustrative.
00:06:34.29 It's human perilipin-1 deficiency,
00:06:38.18 a specific subtype of mutations within this adipocyte triglyceride coat protein.
00:06:45.02 All the members of this family who only carry mutation in...
00:06:47.23 in perilipin-1 all develop partial lipodystrophy,
00:06:51.17 insulin resistance,
00:06:53.10 and the full range of downstream abnormalities:
00:06:56.04 fatty liver disease, cardiovascular disease, etc.
00:06:59.26 The individuals carry... carry heterozygous mutations,
00:07:03.11 which cause one copy of perilipin-1
00:07:06.19 to be made normally
00:07:08.14 and then another mutant copy with an aberrant C-terminal tail.
00:07:11.17 So, what's happening in these individuals?
00:07:13.16 The important fact is that perilipin-1
00:07:16.02 is only expressed in white adipocytes.
00:07:18.25 So, here we have a disorder
00:07:21.13 where you simply have one copy of one gene
00:07:24.04 made only in one tissue -- the white adipocyte --
00:07:26.16 and yet every feature of the metabolic syndrome
00:07:29.07 is present in these severely affected individuals.
00:07:31.27 What's happening?
00:07:33.13 Well, what's happening is as follows.
00:07:35.03 Here's where perilipin-1 is.
00:07:36.24 It sits on the surface of the lipid droplet in the white cell
00:07:38.23 with its partner molecule, CGI58.
00:07:41.03 And when you're making fat... when you've eaten,
00:07:44.08 your lipid droplet is concerned with making fat,
00:07:46.22 and the breakdown enzymes, ATGL and HSL,
00:07:49.21 are kept away from the lipid droplet.
00:07:53.00 Then, when you fast overnight,
00:07:56.00 the hormonal milieu of fasting, and indeed sleeping,
00:07:59.10 induces hormonal changes in the body
00:08:01.07 which induce phosphorylation changes
00:08:03.16 within the adipocyte.
00:08:05.06 The C-terminal phosphorylation site in perilipin-1
00:08:09.18 knocks off the binding site for CGI58,
00:08:13.01 which then goes zipping around the surface of the...
00:08:17.04 of the white fat droplet and grabs ATGL,
00:08:20.00 the initiating lipase,
00:08:22.26 and that starts to break down the triglyceride droplet.
00:08:25.23 Then, at the same time,
00:08:27.13 the second phosphorylation site, nearer the N-terminus of perilipin,
00:08:31.19 binds hormone-sensitive lipase, the second initiat...
00:08:35.21 the second lipase.
00:08:37.10 And then the beautiful cascade of lipolysis
00:08:39.29 starts to break down the triglyceride,
00:08:41.26 down to three individual fatty acids.
00:08:45.15 So, that's happening in all of you,
00:08:48.00 in everybody listening to this talk,
00:08:49.18 in between their fed and their fasted state.
00:08:51.23 And that is natural metabolic health.
00:08:53.23 The unfortunate people who have this C-terminal perilipin-1 mutant
00:08:57.20 have, as you see in the bottom here, with the green box...
00:09:00.09 they've lost that phosphorylation site at the C...
00:09:03.06 at the C-terminal end of perilipin-1.
00:09:05.16 And throughout the day -- irrespective of whether they've been fed or fasted --
00:09:11.27 CGI58 is free to roam and...
00:09:14.14 and binds promiscuously to ATGL.
00:09:17.20 And therefore, throughout the day, whether you're fed or not,
00:09:19.27 your fat cell is breaking down triglycerides
00:09:22.17 and releasing molecules of fatty acid.
00:09:24.27 Now, remarkably, this in itself is enough
00:09:28.07 to cause every single feature of the metabolic...
00:09:30.28 the metabolic syndrome:
00:09:33.24 Insulin resistance, fatty liver, atherosclerosis.
00:09:36.17 This is a rare condition,
00:09:40.01 but I think one which is really illustrative of the very important point
00:09:42.21 that the health of your white fat cell
00:09:44.11 -- and indeed the health... the healthy dynamic of your white cell fat droplet --
00:09:47.02 is really crucial to your overall, organismal metabolic health.
00:09:53.19 Is this, again, more relevant... outside these rarities?
00:09:58.06 And is it... is this sort of process relevant
00:10:03.07 to the wider population of people with the metabolic syndrome?
00:10:05.08 Well, to address this, we collaborated with our colleagues in the MRC Epidemiology Unit
00:10:09.23 -- whose names are listed here --
00:10:11.27 led by Nick Wareham.
00:10:15.06 And we asked about genetic variation influencing lipodystrophy-like
00:10:20.03 metabolic phenotypes in the general population.
00:10:22.06 So, we looked at people who had high insulin, low HDL/cholesterol,
00:10:25.19 and high triglycerides as a composite index.
00:10:28.18 And in nearly 200,000 people,
00:10:31.02 we found 53 genetic variations in the genome
00:10:34.02 that influenced those traits in the general population.
00:10:38.09 And these are shown in the next slide.
00:10:40.19 Now, on the far left of the slide,
00:10:42.26 in red and blue and red,
00:10:44.12 there are the 53 genetic loci that we found to associate --
00:10:48.14 either red being positive, and blue being negative.
00:10:50.16 And of course, that's how we defined our phenotypes,
00:10:53.09 so of course you see the consistent red, blue, and red.
00:10:56.24 Now, if you go to the further end of the slide,
00:10:59.07 you should be able to see independent populations,
00:11:01.19 where those SNPs are looked at against type 2 diabetes
00:11:05.12 and coronary artery disease.
00:11:06.25 And of course, it's reassuring, scientifically,
00:11:08.21 to find that those genes are associated,
00:11:11.02 in totally independent populations,
00:11:13.13 with these adverse outcomes, these...
00:11:16.05 coronary artery disease and type 2 diabetes.
00:11:17.29 What we found puzzling and exciting
00:11:20.07 is when we looked in the middle of the slide.
00:11:21.27 There, we took independent populations
00:11:23.19 and said, are these variants, these SNPs,
00:11:27.07 associated with more body fat or less body fat?
00:11:29.03 And rather remarkably, you see a lot of blue.
00:11:31.04 And that lot of blues actually tells you
00:11:34.20 that these individuals SNPs and these indivi...
00:11:36.20 the genes, when put together,
00:11:38.18 actually are associated with lower amounts of body fat,
00:11:40.10 not higher amounts of body fat.
00:11:43.14 And this is taken further into an independent analysis
00:11:46.11 in people who have had compartmental measurements of their body fat
00:11:49.23 using DEXA scanning,
00:11:52.06 so we can actually measure the fat in the arms, trunk, etc.
00:11:54.12 And again, looking at the genetic factors
00:11:56.19 that put you at risk of developing
00:11:59.14 these metabolic syndrome phenotypes,
00:12:01.24 what we found quite remarkable
00:12:04.17 was down at the bottom of the slide, here.
00:12:06.03 We see that individuals carrying more of these risk alleles
00:12:08.24 actually had less fat...
00:12:10.13 less fat in the gynoid distribution, i.e., buttocks and thighs,
00:12:14.08 less fat in the legs,
00:12:16.02 and really, not very much difference in the places
00:12:18.17 we thought would be really important,
00:12:20.13 the visceral fat... only a little bit of an increase in the...
00:12:22.15 in the visceral fat.
00:12:23.28 This is... the changes in body fat
00:12:26.22 are driven much more by lower body fat in the legs and thighs.
00:12:31.25 And indeed, when you take these SNPs
00:12:34.14 and using bioinformatic tools
00:12:36.15 ask where these variants are expressing their actions most,
00:12:40.13 you see, quite remarkably,
00:12:42.07 that they do so in adipocytes and adipose tissue.
00:12:45.08 In other words, we chose these variants
00:12:47.13 in a completely hypothesis-free way.
00:12:49.25 We didn't ask the adipose tissue,
00:12:51.18 was it abnormal?
00:12:53.01 The adipose tissue spoke to us spontaneously.
00:12:56.14 And then, when we take some of those variants and manipulate them,
00:12:59.29 we can show that manipulating these genes
00:13:02.05 influences adipose tissue fat accumulation.
00:13:07.17 So, in a further body of work led by Luca Lotta
00:13:11.03 and Nick Wareham,
00:13:12.19 they asked I think what is a very interesting
00:13:14.15 and rather piquant question.
00:13:17.05 And the question really is,
00:13:18.28 is it worse to have a small bottom or a big belly?
00:13:21.23 And they separated out those variants.
00:13:23.18 In red are the variants that... that cause...
00:13:29.05 that are selectively associated with a waist ratio.
00:13:33.09 And in blue are the variants associated with only hip ratios.
00:13:38.24 So, you can see in the bottom there that fasting insulin,
00:13:41.07 a measure for insulin resistance,
00:13:43.02 is much more strongly associated with the hip SNPs
00:13:45.27 rather than the waist SNPs.
00:13:47.29 And then, when it comes to the bottom-line data,
00:13:50.04 type 2 diabetes risk is greatly influenced by hip, much more than waist, circumference.
00:13:56.02 So, what's actually determining these risks of diabetes
00:13:58.12 is not the big belly;
00:14:00.00 it's the absence of fat on the buttocks and legs,
00:14:03.05 much more so than the larger belly.
00:14:05.11 They're much more equal when it comes to coronary artery disease,
00:14:07.21 but for diabetes it's the absence of fat in buttocks and thighs
00:14:11.13 that's much bigger...
00:14:13.11 having a much bigger influence than the positive presence of fat
00:14:15.19 in the visceral deposits.
00:14:18.29 So, that really led me to develop
00:14:22.04 a kind of useful model, an explanatory model,
00:14:24.17 or at least an illustrative model, for what's going on.
00:14:28.00 So, you can think of this as a...
00:14:30.14 as a bathroom in a hotel you happen to go into that...
00:14:32.26 somebody's left the plug out, and somebody's left the...
00:14:35.02 left the tap on.
00:14:36.28 But that's fine, because the bathroom is...
00:14:38.16 you know, it's an old B&B.
00:14:40.09 It's got a [unknown] carpet,
00:14:41.28 and the carpet's perfectly healthy because the flow is fine.
00:14:44.28 You've reached a steady state,
00:14:46.12 and you've got a perfectly healthy, non-soggy carpet.
00:14:51.01 But we often think of metabolic disease
00:14:53.14 as being due to too much energy,
00:14:55.15 i.e., pouring too much in,
00:14:58.22 or a decreased energy out, restraining how much we let out.
00:15:02.00 And of course, then, you overfill your bath
00:15:04.26 and you get a terrible, messy situation.
00:15:08.14 And that's kind of how we tend to think about metabolic disease.
00:15:11.13 I think what our data, both in lipodystrophy
00:15:13.29 and now... and al... now, in the common forms of insulin resistance,
00:15:17.10 is showing that... that really we haven't paid enough attention
00:15:22.08 to the size of the bath.
00:15:23.23 In other words, as well as how much energy we take in
00:15:26.11 or how much energy we expend,
00:15:28.07 we differ between us in our abilities
00:15:30.24 to safely expand our adipose depots,
00:15:32.26 so that some individuals become severely insulin resistant
00:15:35.22 and diabetic
00:15:37.28 at rather low levels of energy imbalance
00:15:39.16 whereas others are capable of tolerating
00:15:44.12 a large amount of obesity without developing any metabolic complications.
00:15:48.18 So, here's one example
00:15:52.00 of what one might be able to do
00:15:53.26 in individuals who've got a small bath.
00:15:55.28 We look after, in our clinic,
00:15:58.26 patients with severe insulin resistance and lipodystrophy.
00:16:01.01 Here's an example of one such patient and a DEXA scan.
00:16:03.22 This person has very low fat in their...
00:16:05.17 in their legs and limbs compared to their central depots.
00:16:08.22 They have severely uncontrolled diabetes
00:16:11.29 on hundreds of units of insulin a day.
00:16:15.29 And what we've done in this individual is undertake bariatric surgery.
00:16:21.09 But this individual is only very modestly obese
00:16:23.21 -- he wouldn't be really defined as severely obese --
00:16:25.14 but has got a really poor ability to handle any excess calories.
00:16:29.06 Now, what bariatric surgery does
00:16:31.18 is it chronically suppresses food intake,
00:16:33.15 largely through suppressing appetite
00:16:35.12 and changing the signaling to the brain.
00:16:36.23 And just within a few months...
00:16:38.29 here's April, just a few months after the surgery in December.
00:16:40.24 That individual has lost a large amount of their central body weight.
00:16:45.12 But effectively, what they've done is turned the tap off
00:16:48.14 on their small bath.
00:16:50.00 And rapidly, they have... their diabetes has gone away, effectively.
00:16:53.01 They're off... they were on hundreds of units of insulin.
00:16:55.22 They're now on no units of insulin.
00:16:57.14 So, individuals with this very limited capacity
00:16:59.29 to store adipose tissue safely
00:17:01.26 are particularly bet...
00:17:03.20 have great benefit from bariatric surgery,
00:17:06.10 even, indeed, more so than individuals with severe obesity.
00:17:09.22 And now, this has been spun out in much broader clinical studies
00:17:13.29 to see how... how widely applicable this is
00:17:17.02 in partial lipodystrophy.
00:17:20.16 We're now moving, in our next scientific phase,
00:17:23.06 away from, if you like,
00:17:25.03 vague hand-waving about these sorts of genes
00:17:26.29 that influence adipose mass,
00:17:28.24 trying to drill down and find precise molecular regulators of fat cells,
00:17:33.18 particularly so that...
00:17:35.10 if we can identify those, then perhaps they might be therapeutically manipulable.
00:17:37.28 We might be able to use them as therapeutic targets
00:17:40.12 to increase our safe fat cell storage.
00:17:44.03 This is just an overview slide showing that,
00:17:46.15 in using UK Biobank,
00:17:48.07 we can find rare nonsynonymous variants
00:17:50.22 that are strongly associated with waist hip ratio.
00:17:54.03 Because Biobank is now so large,
00:17:55.29 and the sequencing and SNP data is so extensive,
00:17:57.29 we can really start drilling down into individual genes.
00:18:03.09 Here, for example, are some variants in the serine kinase Alk7,
00:18:07.16 encoded by the gene ACVR1C.
00:18:10.13 The two on the right are actually missense variants.
00:18:13.17 They're truly genes that influence...
00:18:16.04 genes that...
00:18:18.21 variants that cause changes in the amino acid sequence
00:18:20.24 in the... in the genes.
00:18:24.12 And looking at the two of them here,
00:18:27.15 N150H is probably a bit less interesting,
00:18:29.14 because it's not so conserved across species.
00:18:31.27 But I195T is highly conserved
00:18:35.15 across many, many species.
00:18:38.01 And if you look at what I95T does,
00:18:40.28 it has a profound structural impact on the putative functions of Alk7.
00:18:45.24 It influences the... the so-called GS domain, here in green,
00:18:50.25 and really would prevent it flipping away
00:18:53.14 when the ligand binds to this receptor,
00:18:56.12 and prevent the access of the next downstream signaling molecules,
00:18:59.19 the SMAD...
00:19:01.16 prevent access to the... to the catalytic loop.
00:19:04.00 So, when we went ahead and reconstituted this mutant
00:19:08.13 -- a very talented postdoc in the lab, Nuno Rocha, did this --
00:19:11.20 and really wanted to see whether this variant
00:19:15.06 truly does influence signaling.
00:19:18.12 And what Nuno showed, in red here,
00:19:20.10 is that this variant,
00:19:22.13 which is associated, as I mentioned, from protection...
00:19:24.15 from protective phenotypes,
00:19:26.24 a low waist hip ratio and protection from type 2 diabetes,
00:19:30.10 actually is a loss of function allele
00:19:33.07 compared to a constitutively active, in gray,
00:19:36.19 and one of the other variants, in yellow,
00:19:38.25 which doesn't seem to have any effect,
00:19:40.25 but the red is our 195T variant,
00:19:42.23 which is markedly impaired in signaling
00:19:45.03 compared to our wild type.
00:19:48.05 So, this is surprising,
00:19:50.05 because in mice, at least,
00:19:52.10 inactivation of Alk7 has been reported to enhance lipolysis.
00:19:55.08 So, we're further working, now, in human adipocytes
00:19:58.07 to see if this finding is different in humans.
00:20:00.10 But I think this data provides evidence
00:20:02.26 that large-scale human sequencing efforts
00:20:04.24 are now empowering the study of human coding variations
00:20:07.28 and their links to phenotype.
00:20:09.20 And these rare missense and nonsense variants
00:20:11.22 can now be pretty unequivocally
00:20:14.01 associated with human phenotypes.
00:20:16.13 And these were provide an...
00:20:17.28 play an increasingly important role in drug target validation.
00:20:21.22 So, does insulin resistance
00:20:25.11 always affect all insulin tissues equally?
00:20:28.15 And the answer to that is, no.
00:20:31.12 Because glucose is handled in different ways
00:20:34.19 in different tissues.
00:20:36.05 There are, for example, tissues where...
00:20:39.11 where insulin is not required, particularly, to...
00:20:42.23 to get rid of glucose:
00:20:46.23 the brain, the kidney, hemopoietic tissues.
00:20:50.27 But two of the key target tissues I mentioned to you before
00:20:54.24 are liver and skeletal muscle.
00:20:56.21 Actually, insulin works in different ways
00:20:58.28 in these two tissues.
00:21:00.05 In liver, insulin reduces hepatic glucose output,
00:21:03.16 reduces glycogenolysis and gluconeogenesis.
00:21:06.17 But it does so through post-translational modification,
00:21:10.00 by inducing transcriptional events,
00:21:12.20 and, indirectly, through substrate delivery from fat and muscle.
00:21:18.04 Insulin action in skeletal muscle
00:21:20.00 happens in a very different way.
00:21:21.24 There, you get very rapid stimulation of glucose uptake.
00:21:24.22 And here, preformed GLUT4-containing vesicles
00:21:27.22 sitting underneath the plasma membrane
00:21:29.22 rapidly flip to the surface...
00:21:31.00 plasma membrane surface in response to insulin.
00:21:34.07 And so, there are some key differences
00:21:36.12 in how insulin works in...
00:21:38.06 in these two tissues.
00:21:40.16 And this is illustrated by a rare family
00:21:42.16 that we discovered a few years ago,
00:21:44.05 in which... in comparison to most people
00:21:46.29 with insulin resistance,
00:21:48.07 reflected in the blue line above,
00:21:49.23 who have high fasting insulin and high insulin after a meal,
00:21:53.05 these two siblings had extraordinarily high insulin postprandially
00:21:57.08 but normal fasting insulin.
00:21:59.13 So, how could that be?
00:22:01.03 Well, that was because they had a process,
00:22:03.01 and a mutation affecting a process,
00:22:05.24 that only occurs in skeletal muscle
00:22:08.22 and, in part, in fat.
00:22:10.01 And that is the translocation of GLUT4.
00:22:12.02 And there's a key molecule, a so-called Rab GAP, TBC1D4,
00:22:15.18 otherwise known as As160,
00:22:17.18 which is a key regulatory step
00:22:19.21 in regulating how insulin translocates GLUT4 to the plasma membrane.
00:22:23.08 And individuals who are heterozygous loss-of-function for this mutation
00:22:27.12 have a continuous leak of GLUT4
00:22:29.24 to the cell surface
00:22:31.08 so that, actually, when insulin comes to act,
00:22:33.17 there's inadequate intracellular GLUT4 vesicles,
00:22:37.07 and you get a severely impaired postprandial response.
00:22:41.11 Again, we looked for many years and could never find a second family,
00:22:45.02 so this is an exceptionally rare albeit very interesting rarity.
00:22:48.13 But in the last couple of years,
00:22:51.25 it's become fascinating that if you look elsewhere,
00:22:53.20 for example in the Greenland Inuit,
00:22:56.07 the allelic frequency of a very similar mutation
00:22:59.15 is 17%.
00:23:00.29 A very large number of Greenland Inuits
00:23:03.02 carry a very similar mutation.
00:23:05.01 And indeed, in those,
00:23:07.07 you can see that those that carry two copies of that
00:23:10.20 have a much higher 2-hour glucose
00:23:12.27 than individuals who carry one or no copies of that... of that.
00:23:16.22 So, a rarity in the UK has become
00:23:20.12 a phenomenon of epidemiological proportions in another population.
00:23:23.05 And that's another lesson I think we're learning in this field:
00:23:26.06 the importance of studying rare population isolates,
00:23:28.23 and how illuminating they can be,
00:23:31.08 and how different from each other the architecture
00:23:34.01 of genetic variation causing disease
00:23:36.16 can be between these populations.
00:23:38.23 So, the carriers here, interestingly,
00:23:40.18 also have marked postprandial hyperinsulinemia.
00:23:43.16 And many people have thought that if you had,
00:23:47.14 for example, impaired insulin signaling in skeletal muscle
00:23:50.03 and had very high insulin,
00:23:51.26 that might put your weight up.
00:23:53.06 These individuals have no difference in body weight
00:23:54.23 and, indeed, no differences in circulating lipids,
00:23:57.02 making us think again about what hyperinsulinemia
00:24:00.11 might actually be doing to things like body weight and lipids.
00:24:06.13 So, I'm gonna end with an overview, really,
00:24:11.16 of how organs work together.
00:24:12.29 The wonderful thing about endocrinology and metabolism
00:24:15.11 is they're really not conditions of cells;
00:24:17.03 they're conditions of systems.
00:24:18.25 And you have to understand how the system works
00:24:22.14 to really get a true understanding and true knowledge of disease pathophysiology.
00:24:28.20 So, if you were gonna avoid getting type 2 diabetes,
00:24:30.19 how might you go about it?
00:24:32.15 Well, first of all, you'd maintain energy balance.
00:24:34.26 You wouldn't let your energy in get more than your energy out.
00:24:37.12 And that, as we've discovered from our genetic studies, it...
00:24:40.27 not discussed with you today, but in other contexts,
00:24:44.20 is really a job of the brain and the gut-brain interface.
00:24:48.00 So, the brain is really the most important organ
00:24:50.20 determining who is perpetually hungry,
00:24:53.11 who is easily satiated --
00:24:54.28 the variation between individuals in energy balance.
00:24:58.02 The next step is that of the...
00:25:02.05 to store... if you...
00:25:04.13 if you can't manage to stay in energy balance
00:25:06.04 and you do accumulate an energy imbalance,
00:25:07.22 then you're fine so long as you can safely store that in fat.
00:25:12.04 So, adipose tissue has really turned out to be
00:25:15.24 a very important... and not just a passive store of lipid
00:25:18.22 but a very important determinant of how we...
00:25:22.09 how our metabolic balance or imbalance can be main...
00:25:25.23 can be maintained.
00:25:27.21 If we can't store lipids safely in our adipose tissue
00:25:31.02 and it goes to liver and muscle,
00:25:33.03 then a key factor there is
00:25:36.07 whether that lipid produces insulin insensitivity of glucose metabolism.
00:25:41.01 There, we find, at the moment,
00:25:43.04 fewer genetic variants that determine that factor.
00:25:45.05 That may be a methodological issue.
00:25:46.22 I'm sure these processes are key.
00:25:49.27 But some individuals become insulin resistant,
00:25:52.08 some becomes severely insulin resistant,
00:25:54.06 and yet some severely insulin resistant individuals
00:25:57.07 don't get type 2 diabetes.
00:25:58.21 And in work, again, I haven't discussed today,
00:26:01.17 the key transition point between those individuals
00:26:05.05 who are insulin resistant and those who then decompensate to diabetes
00:26:10.00 is the genetic architecture of your pancreatic beta cells.
00:26:11.28 Work from colleagues in Oxford, Exeter,
00:26:14.18 and elsewhere around the world...
00:26:16.20 have really done beautiful science
00:26:18.29 showing how important the genetic health of your pancreatic beta cells
00:26:22.07 is to determine whether you transition to type 2 diabetes or not.
00:26:27.03 I'll return to the immune system and the host defense.
00:26:31.29 Much work in mice has really illum...
00:26:33.15 illustrated a critical role, and suggested a critical role,
00:26:37.26 for the immune system in maintaining metabolic health.
00:26:40.29 And yet, much of our genetic work
00:26:44.00 and, indeed, very much pharmacology
00:26:46.10 really hasn't come up with that much human evidence
00:26:48.19 that this is terribly important.
00:26:50.18 I mean, for example, if you look,
00:26:54.28 as Bernstein's lab did a few years ago,
00:26:56.22 at the... at the genetic SNPs...
00:26:59.05 at single nucleotide polymorphisms
00:27:01.22 associated with a variety of inflammatory
00:27:04.12 and a variety of metabolic phenotypes,
00:27:06.26 there's really very little overlap.
00:27:08.09 There's almost a complete separation
00:27:10.16 between the inflammatory diseases and the metabolic diseases.
00:27:12.13 And in the same paper,
00:27:15.03 looking in a different way at which tissues might be implicated through...
00:27:18.07 through genomics and transcriptomics,
00:27:20.15 you can find, for example,
00:27:22.17 in the top left-hand corner here,
00:27:25.01 Bernstein's lab is looking at neurological conditions
00:27:27.29 and showing that they cluster around brain tissue --
00:27:31.03 not surprisingly.
00:27:32.25 And then a whole range of immune conditions.
00:27:34.19 Very, very wide... widespread immune conditions.
00:27:37.06 And of course, again, unsurprisingly,
00:27:39.05 the genetic variation influencing them
00:27:41.16 is having its major effect on immune cells --
00:27:44.04 on lymphocytes and macrophages.
00:27:46.16 Again, like with the SNPs and the disease associations,
00:27:48.24 metabolic disorders such as high triglycerides,
00:27:52.04 low HDL, fasting glucose, etc,
00:27:56.00 tend to cluster away from the immune phenotypes.
00:27:59.20 So, I would say that it's still
00:28:03.09 an interesting hypothesis
00:28:05.24 that our host defense and immune system
00:28:08.03 is critically important for metabolic health,
00:28:10.04 but we still need more and more detailed genetic investigation,
00:28:13.19 and more pharmacological proof,
00:28:15.29 before those undoubtedly beautiful murine experiments
00:28:18.18 are seen as deeply relevant to human disease.
00:28:24.17 So, finally, how can we use this information
00:28:27.23 to prevent insulin resistance.
00:28:29.22 We are... at the moment,
00:28:31.13 we know that we need to reduce calories in.
00:28:33.09 And that's easy to say.
00:28:35.15 We can tell people to lose weight and reduce food.
00:28:38.26 But sometime, now,
00:28:41.01 we get to a stage where drugs will help.
00:28:42.24 And there is an...
00:28:44.18 and there are exciting developments in anorectic drug developments,
00:28:46.18 and I think this is likely to get more effective.
00:28:50.04 We can tell people to exercise more,
00:28:52.22 increase their expended calories.
00:28:54.00 There's much work going on trying to develop drugs
00:28:57.14 to increase brown adipose tissue thermogenesis, for example
00:29:00.17 , or exerc... act as exercise mimetics,
00:29:02.21 but they're some way behind the development of drugs
00:29:05.00 for suppressing food intake.
00:29:07.25 What about making our bath bigger?
00:29:09.26 Can we increase safe storage of calories in adipose tissue?
00:29:13.18 Well, actually, one class of drugs,
00:29:15.24 one of which is still available,
00:29:17.06 has proved the concept.
00:29:18.20 Thiazolidinedione drugs do indeed improve insulin sensitivity
00:29:21.08 while at the same time increasing your fat mass.
00:29:24.03 Sadly, with some of the drugs,
00:29:25.22 there are other safety issues.
00:29:27.07 But I think we have got proof
00:29:29.15 that if we can cleverly target adipose tissue
00:29:31.20 to make it a safer store for our fat,
00:29:34.03 that is another route towards rendering individuals
00:29:39.01 metabolically healthier.
00:29:41.05 So, I'd like to finish by thanking my colleagues and collaborators,
00:29:44.07 our referring physicians, our funders,
00:29:46.15 but particularly, our patients, participants, and families,
00:29:49.07 without whom we would not have had a research program.
00:29:51.22 Thank you.

Videos in this Talk

Part 1: The Causes of Obesity: Why Isn’t everybody fat?
Audience:
- Student
- Researcher
- Educators of H. School / Intro Undergrad
- Educators of Adv. Undergrad / Grad
Part 2: Why Does Obesity Lead to Adverse Health Outcomes?
Audience:
- Student
- Researcher
- Educators of H. School / Intro Undergrad
- Educators of Adv. Undergrad / Grad

Speaker: Stephen O'Rahilly

Total Duration: 1:01:13

Recorded: September 2019

All Talks in Human Disease

Talk Overview

Easy access to nutrients has contributed to the increase in obesity in the human population. But, what is obesity and why isn’t everybody fat? Dr. Stephen O’Rahilly provides a biomedical perspective of obesity, and evaluates which genes could potentially shift the balance towards obesity. As he explains, one becomes obese when the balance between energy intake and energy spent is shifted. Surprisingly, mutations that lead to obesity in humans aren’t in genes involved in metabolism and energy storage, but failure in satiety signals in the brain that result in people eating too much. The excess of energy intake over energy expenditure leads to obesity.

What is the consequence of obesity in human health? Physically, obesity can result in lower mobility and sleeping disorders. But, in humans, the link between obesity and metabolic diseases isn’t straightforward. For example, not everyone that’s obese becomes insulin resistant. As O’Rahilly explains, the probability of an obese individual to have a metabolic disease is linked to the capacity of adipose tissue to store the extra fat. Mutations that decrease fat storage in adipose tissue increase the chance of metabolic diseases, like insulin resistance, even when the person is not obese.

Speaker Bio

Stephen O'Rahilly

Dr. Stephen O’Rahilly is a professor of Clinical Biochemistry and Medicine and Head of the Department of Clinical Biochemistry at the University of Cambridge where he also directs the MRC Metabolic Diseases Unit in the Wellcome-MRC Institute of Metabolic Science. He qualified in Medicine from University College Dublin, and continued his post-graduate training at Oxford… Continue Reading