Tuesday, July 2, 2013

The Genetics of Obesity, Part II

Rodents Lead the Way

The study of obesity genetics dates back more than half a century.  In 1949, researchers at the Jackson Laboratories identified a remarkably fat mouse, which they determined carried a spontaneous mutation in an unidentified gene.  They named this the "obese" (ob/ob) mouse.  Over the next few decades, researchers identified several other genetically obese mice with spontaneous mutations, including diabetic (db/db) mice, "agouti" (Avy) mice, and "Zucker" (fa/fa) rats.

At the time of discovery, no one knew where the mutations resided in the genome.  All they knew is that the mutations were in single genes, and they resulted in extreme obesity.  Researchers recognized this as a huge opportunity to learn something important about the regulation of body fatness in an unbiased way.  Unbiased because these mutations could be identified with no prior knowledge about their function, therefore the investigators' pre-existing beliefs about the mechanisms of body fat regulation could have no impact on what they learned.  Many different research groups tried to pin down the underlying source of dysfunction: some thought it was elevated insulin and changes in adipose tissue metabolism, others thought it was elevated cortisol, and a variety of other hypotheses.

At the same time, several groups were researching a fascinating new "anti-lipogenic factor" (also "satiety factor") they had identified by literally fusing together obese and normal rats, allowing their circulation to (very slowly) communicate (1).  Their results suggested the existence of a previously unidentified, powerful circulating factor that regulates food intake and body fatness, and they were able to rule out insulin, glucose, fatty acids, cortisol, and a variety of other potential contenders.  Furthermore, their findings suggested that ob/ob mice lack the anti-lipogenic factor, db/db mice lack its receptor, and the factor acts primarily in a brain region called the hypothalamus (2).  Yet the identity of the factor remained unknown until 1994.

Realizing that a full understanding of obesity in ob/ob mice would require identifying the mutation, a research team led by Dr. Rudolf Leibel set out to identify it through a laborious process called positional cloning.  In 1994, this led to the cloning and sequencing of the ob gene (3), which encoded a previously unknown protein of 16 kilodaltons.  They named it leptin, after the Greek word "leptos", meaning "thin".  Here is the full abstract of the paper:
The mechanisms that balance food intake and energy expenditure determine who will be obese and who will be lean. One of the molecules that regulates energy balance in the mouse is the obese (ob) gene. Mutation of ob results in profound obesity and type II diabetes as part of a syndrome that resembles morbid obesity in humans. The ob gene product may function as part of a signalling pathway from adipose tissue that acts to regulate the size of the body fat depot.
Further work confirmed that leptin is produced primarily by fat cells and acts in the brain to constrain food intake and body fatness (4).  Remarkably, all of the original single-gene mutations that cause rodent obesity ended up being in the leptin signaling pathway.  ob/ob mice lack leptin, db/db mice and fa/fa rats lack the leptin receptor, and Avy mice have a mutation that mimics the effects of leptin deficiency in the brain.  The obesity, elevated insulin, and alterations in fat cell metabolism in these models were all downstream consequences of defects in the leptin signaling pathway-- via the brain.

Humans Follow

Shortly after the cloning of the leptin gene, researchers identified a family of humans that also lacked leptin function (5), providing "the first genetic evidence that leptin is an important regulator of energy balance in humans".  Not only were they obese, with an abnormally large appetite, but treating them with leptin normalized their appetite and returned them to a normal weight (6), as shown in the photo to the left (6b).  As of 2013, a number of human families with obesity due to single-gene mutations have been identified.  If we consider only those mutations that cause obesity without causing significant developmental abnormalities, all of them turned out to be in the leptin signaling pathway-- either in leptin, the leptin receptor, or the brain circuits that respond to leptin and related signals (7)*.  As was the case in rodents, spontaneous mutations in humans pointed to the leptin-brain axis as the primary regulator of body fatness.

More recently, researchers have performed large-scale genetic screens on people who have severe or early-onset obesity to see if some cases can be attributed to variance in specific genes.  About 4 percent of severely obese people have a mutation in the melanocortin receptor 4 (MC4R) gene that causes it to lose function (8), and two recently published papers identified a loss-of function variant of the gene SIM1 in another subset of early-onset obese subjects (9, 10).  MC4R is a receptor for alpha-MSH**, the product of leptin-responsive POMC neurons, and SIM1 is an important protein for the development and function of the paraventricular nucleus of the hypothalamus, a major target of POMC neurons.  In other words, they are both part of the same system in the brain that regulates body fatness in response to leptin and other signals.  Both the MC4R and SIM1 variants cause an increase in food intake due to a defect in satiety (11).  For people with these variants, achieving real leanness is unlikely.  Other studies have also uncovered mutations in genes associated with the brain regulation of body fatness in severe early-onset obesity (11b).

So far, I've described rare mutations that lead to severe obesity.  These mutations only account for a very small fraction of the obese population.  To understand what genes are involved in common obesity, we'll have to turn to another method: genome-wide association studies (GWAS).  The GWAS method takes advantage of the fact that everyone's genome is a little bit different.  By sequencing these areas of difference between people***, they can associate them with specific traits, for example, obesity.  This allows researchers to "map" sites of particular importance to the trait in question, which tells us something about what biological processes are relevant to the trait.  For example, diabetes-linked regions are mostly associated with genes affecting the pancreas, as one would expect (12)  though some obesity genes do show up as well****.

The findings of obesity GWAS studies are basically consistent with the other evidence described above (12b).  For many of the identified regions, we don't know which gene is involved.  For the genes that we have identified, most of them are involved in brain function, particularly the leptin-responsive hypothalamus.  Here's a quote from a review paper that sums it up (13):
...when we look at the information gleaned from the past 15 years of molecular genetic activity we cannot avoid concluding that, as much as type 2 diabetes is clearly a disease in which pancreatic beta-cell dysfunction is a critical element, obesity is a condition in which inherent genetic predisposition is dominated by the brain.
That being said, GWAS studies have failed to identify the majority of the genetic differences that account for the 70 percent heritability of body fatness (less than 3% accounted for).  We have enough information to know what types of biological processes are involved in common obesity, but we don't know all the details yet.  As the old saying goes, "more research is required"!

What does it Mean?

The genetic data converge powerfully with other fields such as neurobiology, endocrinology, and physiology, together demonstrating conclusively that:

  1. The brain is the main regulator of body fatness.
  2. The brain regulates body fatness in response to internal signals of energy stores, particularly leptin.
  3. Genetic variability in body fatness is likely predominantly determined by genetic differences in brain function, particularly the hypothalamus.

In the next post, I'll explain why genes are not (usually) destiny.

* Those that do cause deformity also involve brain energy balance circuitry (14).

** Also AgRP, which is an inverse agonist at the MC4R and increases food intake.

*** Typically, single-nucleotide polymorphisms.

**** E.g., FTO, the #1 obesity GWAS hit.


Franc said...


thanks for yet an other excellent article. Looks like you left your starting point at the end of it though :)

So can Cartman now say he has fat genes?

CLB said...

Great read. Thanks Stephan.

Anonymous said...

Definitely very interesting.

I look forward to your next post. Odds are I will have more than a few things to say. :)

Unknown said...

Stephan thank you so much for taking the time to do this. After more than 3 years, your blog is still one of the few that I read. Keep up the great work!

Unknown said...

Thank you for these posts. My daughter is 2 years old and seemingly has unlimited appetite. At 7 weeks old she was almost at the 100th percentile for weight on breast milk. By 6 months old she was well off the charts. I read an article about the MC4R mutation and have wondered since if she has inherited it - her nana on her dads side has been obese since late childhood but also has low blood pressure which apparently fits with this. And then I am we'll managed but realise that I never really know what being full feels like. Hmm. Anyway, I have extensive knowledge but have struggled to keep her weight down which makes my heart break for those parents with kids who are born predisposed to gaining weight with less knowledge than I hold. They are blamed when they really shouldn't be - 'moderation' does not stop these kids from getting overweight. I have tried a few things with my daughter but lately a Kitavan inspired sort of diet is working for her - a diet based on things like pumpkin, banana with small amounts of butter or coconut oil, and a little bit of meat or fish or eggs at lunch and dinner. I hate parties because she could easily consume 1000s of calories, be refluxy but still ask for more food. She is 3 next month and is a very bright girl and is now more like the 85th percentile for weight. thanks to her diet I think she is getting all the things for her growing brain too.
Sorry for the ramble but thank you for all of your blog, it has helped me with the struggles with my daughters appetite very much. Looking forward to your next post.

Stephan Guyenet said...

Hi Franc, CLB, jayman, TheRosenfeltc,

Thanks, glad you found it useful.

Hi Ness,

Interesting; it is possible that she has a genetic predisposition to obesity. Glad you've found a way to keep it under control.

Jenny said...

I noted a very interesting paragraph in this report about the recent Nature paper that describes a major breakthrough in understanding Mitrochondrial function. (view HERE)
"During the study the team also made the unexpected discovery that the most widely used mouse strain for laboratory genetic analysis is unable to correctly assemble the respiratory supercomplexes. This raises serious questions about the validity of extrapolating results obtained with these mice to humans."

I wonder how much impact this finding has on mouse-related diet research--and I wonder even more if this news will get to the people doing that mouse-based research due to how narrow the focus seems to be in many specialites. Will they even hear of this new finding?

Robert said...

Thanks for the interesting article, Dr. G. Looking forward to hearing what the latest hypotheses for environmental triggers of lep. res. are.

Armi Legge said...

Hey Stephan, excellent series so far.

I'm guessing you'll probably cover this, but do you think it's worth obese people getting genetic testing to see if they have a particularly high susceptibility to weight gain?

There is a similar debate in the world of athletic talent development and identification -- whether or not kids should get tested to see if they're "gifted."

It seems like it could be helpful in providing some answers and potentially some motivation, but on the other hand it seems that genetic testing can also be extremely inaccurate and nonspecific on an individual basis.

It also seems like being severely overweight would be enough of a reason to make a diet and lifestyle change, but it obviously isn't for many.

Thanks again for your work,

- Armi

Unknown said...

Excellent review of the origin of genetic research in obesity. You painted quite a convincing picture on the importance of the brain in obesity and the metabolic disease that arise from obesity. I am greatly looking forward to part III. Thanks for your incredible contributions and looking forward to your talk in a few weeks at AHS.


Unknown said...

Thanks Stephan, can't wait for the next installment and I echo the sentiment of many that we appreciate what you do on this blog.

Does this mean that for many after obesity has set in that an epigentic even occurs?

Thanks for post Jenny, I would like to see the entire study!

Anonymous said...

Hi Stephan,

I am just stopping by this one time to say hello and post something to benefit the public. Your blog is excellent as usual, even over the last year. ;)

I've talked with the best of the best in physics, including Dr. Gavin Crooks ( the non- equilibrium thermodynamics expert who several M.I.T. guys recommended to me).

He said that " You are correct in that the human body is an open, non-equilibrium system. However,I doubt that there is any single equation that can characterize the loss/gain of body fat and muscle. The loss and gain of body fat/muscle are extremely complex biochemical processes that are best understood within the framework of physiology, rather than basic physics."

It is one of my pet peeves that the Internet salesmen erroneously use the First Law to blame obese people. It is complete misuse and as scientifically erroneous and erroneous can be. They are going far beyond its reach and scope. Yes, it is valid for life, but it says nothing about the causes of obesity. Dr. Krauss, Dr. Tyson and Dr. Susskind all agreed with me.

I have also spoke with Dr. Leibel and he told me that "80 to 90% of the variance in obesity can be be ascribed to genetic factors."

All these top obesity scientists acknowledged that "the body truly has a mind of its own regarding your weight." The body never adjusts to being in a chronic weight reduced state( the brain does not like this weight loss)- and this effect persists and does not go away even after 8 years- and probably the rest of your life, to the best of Dr. Leibel's knowledge. This is bad news. But this knowledge will eventually lead to treatments.

The Internet salesmen gurus' beliefs that severe obesity is solved by "motivation" reveals a less than nursery school type understanding of the problem. They are not understanding the set point thresh hold that the body establishes around puberty for body weight. Dr. Leibel suggests trying to prevent the increase in set point in the first place rather than trying to do the currently near impossible-
( i.e. lower the "thermostat" later in life once established). Dialing down this thermostat in the hypothalamus is one of the most important things for us to figure out. We need this for an effective treatment for obesity that works- long term.

The salesmen want to blame the victim so they can SELL them their worthless products etc.The worlsd would be a better place if the public were better informed against these hucksters and charlatans.

Thanks for the work you do. As you know, I support it. :)

Take care, Stephan.

Wishing you the best,

Anonymous said...

Hi Stephan, great writing. Leptin is certainly a major hub in nutrition and energy regulation (hence why it's considered a "partner" with mTOR). Here's the thing about the language of the framework. In medical approaches we seem to think we have a susceptbility or some kind of inherent weakness to a disease. It's thought of as a defunct "runs in the family". This may be true on a purely genetic deletion type situations. However, genes don't typically program for dysfucntion, they program for function. Studying stress mechanisms we have bidirectional, multifaceted "trade-offs" that occur that can give a benefit AND a susceptibility (like if you need more fat for your myelination, you'd have mechanism that could more easily be disrupted). So the question would be what gain do we get from the genetic profile that also creates susceptibility to stress (leptin can be regulated genetically early in life via nutritional status (n-3s) combined with stresses and programs an adaptation to greater sensitivity to environmental factors), that the body/brain thinks extra energy storage will solve? Food for thought.

Grinch said...


One thing I've been trying to understand better is what causes many of us to binge eat at night. I've never been massively overweight, but just slightly overweight. I've always been very physically active playing sports and even running marathons. What I find is a very powerful short term homeostatic mechanism that seems to kick in every night that I am in a calorie deficit.

Any time I eat well for the day (at an obvious calorie deficit) or burn lots of calories through exercise, I get extremely hungry and binge on the wrong foods. Is this controlled by leptin or some other hormone(s)? Perhaps its food reward, but I suspect not because I can go most of the day avoiding the highly rewarding foods, its not until the calorie deficit occurs that the impulsive eating kicks in.

JWO said...

Some obese people seem to lack muscle, in those cases it seems likely that something as simple as steroids or human growth hormone could help.

Unknown said...

You're correct, this is best seen when people are put on very low calorie diets (VLCD), if done so for long periods whatever that low calorie diet is, (6-800kcals) can become the new maintenance despite the still relatively high body fat. I refer you to Dr. Baron at UCSF for more information on that. Also this is very prevalent in the bodybuilding/competition world, especially amongst females. The body makes adjustments in response to chronic situations. (hyper--hypo energy balance)

I suspect you are staying in a deficit for too long of periods. Re-feeds that are high in carbohydrates are used to increase leptin and can help to break the plateaus of continuous deficits. Lyle McDonald has written books on the subject and has used this strategy for years. The takeaway point is if you are having the type of binges you describe, you may need to eat at or closer to maintenance for a while and schedule in a re-feed from time to time when in deficit.

Obese people have a lot of muscle mass! For many men that's why they don't want to lose a lot of weight, ( I've had them admit to me they like being big, it's because they are strong and they don't like losing that) If you could strip the fat out of an obese person you would find a bodybuilders body underneath all of the fat (so to speak). However, as we know when you stay in a prolonged deficit sufficient to lose the body fat, lean body mass, including muscle tissue is lost as well. Muscle tissue is a great source of energy for the body. This is why it's imperative for someone losing great amounts of weight to engage in resistance training and keep macro nutrients at optimum levels, particularly protein. There are a ton of data on that subject.

Anonymous said...

Normalizing a hyperactive mTOR initiates muscle growth during obesity. David L. Williamson and Joshua C. Drake. Aging (Albany NY). 2011 February; 3(2): 83–84.

Jane said...

There was an interesting programme on British TV recently in which three very fat women were given advice on how to beat their obesity genes. The advice seems to have worked.

'...in a television first, Fat Family Tree sets out to discover if unlocking the secrets of a family’s genes can help provide the answer to their lifelong weight problems. The programme uses cutting edge genetics to decode the genes of an overweight family for whom all other attempts to shed the pounds have not worked.

Discovering how the family’s genes have put them at risk of excessive weight gain is the first step to devising a diet to help them beat their genes. Based on the latest science, the programme’s “gene-busting” diet also promises fail safe diet tips that could help all of us lose weight.

The McConnon family from Stevenage have all spent their lives battling with their weight and failed time and time again to shed the pounds. Like lots of people they believe their family history of obesity could be down to their genes.

Mum Tina (59) and daughters Lisa (37) and Karen (39)are all desperate to lose weight. Tina has already lost both her own mother and her brother to weight related health problems and she's afraid that she’s going to suffer the same fate.

All three take a unique DNA test to find out if the genes they have inherited could help explain their weight problems. The test, devised with Cambridge University’s Dr Giles Yeo, isn’t looking for one ‘fat gene’; it’s looking for variations in more than 70 genes that can increase your risk of being fat in different ways. These genes influence how intensely you experience hunger, how effectively your brain detects the sensation of fullness when you’ve eaten, where in the body you’re likely to store fat, and your sense of taste - giving some people a genetic preference for sweet or fatty foods. ...'

The advice given to the three women was as follows: stop drinking high-calorie drinks, start walking, and replace refined carbs with unrefined ones (eg white bread with pumpernickel). The women lost 20-30 pounds each in four months. One had diabetes, high blood pressure and high cholesterol and doesn't now.

Unknown said...

Jane I would be quite disappointed if I spent the money to have the genetic tests done and found this to be the recommendation!! They could have simply called me or you and got pretty much the same advice!! Which of course is your point!!

"The advice given to the three women was as follows: stop drinking high-calorie drinks, start walking, and replace refined carbs with unrefined ones (eg white bread with pumpernickel). The women lost 20-30 pounds each in four months. One had diabetes, high blood pressure and high cholesterol and doesn't now".

Jane said...

Hi Mark
Here's what Tina McConnon says in an interview.

What did they tell you once you got the results of your gene test on the programme?

Well that was really quite complicated because they tested about 76 genes, so that's really quite involved. As far as I'm aware, we don't tend to fill up as other people do. The genes that we've got are linked to being more hungry.

So is it a variety of different genes that affect you in different ways?


And does knowing how your genetic make-up affects your weight make it easier to control your weight?

Well it gives you an idea because you think 'why am I like that?'. So at least you can say 'well, that's because of that', and then you have to battle against it.

Since I've been on the diet I haven't really felt that hungry because we've swapped the foods that we were eating, like white bread and white pasta, to the darker varieties and organic and wholemeal, and we're eating more beans and lentils and things that we weren't eating as much of, and they tend to fill you up more because they're what's called fermentable carbs.

So they're specifically chosen for you because of your genetic make-up?

Yes, that's right.

How easy was it to stick to the diet plan that you were given?

At the beginning it was a little bit hard, but it gets easier once you get to grips with it. We're weighing our food. You're only allowed a certain amount, and I was on 1500 calories a day, so you have to look at what you're eating.

I cut out things like sausages and bacon, and stuck more to chicken and turkey, and we eat more eggs. We weren't having sufficient dairy produce in our diet apparently. They found out quite a lot about us really, with all those tests!

Were you surprised by anything you found out, or by anything you were allowed to eat?

A lot of it was surprising. I was surprised because I thought I was eating quite a healthy diet, but when I look at it now it really wasn't. And portion sizes: I was eating far more than I probably should.

But the portion sizes that I'm eating now, when you put them on the plate you think, 'Oh my goodness, that's not going to fill you up', but it does. Because you've replaced it with something that does fill you up a bit more, like porridge or oats or something like that, rather than a bowl of sweet cereal.

BTW I got the numbers wrong about how much weight they lost. It was between 1.5 stone and 3 stone, ie 21-42 pounds, not 20-30.

Unknown said...

Thanks Jane for posting.

Again it's the same diet advice they'd get from me or you most likely. It doesn't take genetic testing to determine that some people simply cannot eat the same amount of calories daily as others and be lean. Many I know that are very educated with nutrition in the exercise industry disagree, as do others from different fields associated with this topic, but it's true for some no doubt. And some people figure this out at an early age, resist weight gain and simply figure out ways to eat at whatever their maintenance intuitively if you will. Many do not and gain substantial body fat, after that happens it's very difficult to correct for them.

~MyGalSal~The "Bird Whisperer" said...

I am very interested in reading this blog and look forward to hearing about your research. I could use some helpful information on this subject.

Jane said...

I think there is an experiment that needs to be done here. What if the women had not deliberately restricted calories but had done the other things? Would their calorie intake have decreased by itself?

My impression from what Tina McConnon says is that she needed to know she has 'obesity genes', to motivate her and make the battle worth fighting. What I would like to know is whether it really needs to be a battle.

What she was not told by the experts is that her new diet contained far more of the minerals mitochondria need. I know from my own experience that eliminating mineral-depleted carbs from your diet can cure chronic fatigue. I suspect obesity and chronic fatigue are two sides of the same coin.

Grinch said...

"You're correct, this is best seen when people are put on very low calorie diets (VLCD), if done so for long periods whatever that low calorie diet is, (6-800kcals) can become the new maintenance despite the still relatively high body fat."

I don't think anybody (at least of a normal height) in the history of mankind has demonstrated a maintenance of 6-800 kcals. Am I wrong about this?

Unknown said...

Jane I agree with you but clearly for many or most it is a battle. The story was a good one and if it took the test to motivate them, then so be it and good for them.

Grinch 6-800 is an example but it can be 1000 depending on the individual and it's not something that will happen to everyone on VLCD. It does happen and not just those with a high BF%, it's seen in the lean competitive bodybuilding group as well. If they jump right back to something that should not represent their maintenance they gain body fat fast. It takes careful reverse dieting to solve the problem, and for some it can take a long time incrementally adding calories in. I have personally seen this issue. It seems to be more prevalent for females for some reason.

Franc said...

LOL saw this post and went "I know these mice!"


Laurie said...

Not all obese people have a lot of muscles. Growth hormone does help increase muscle mass in some obese individuals. And I disagree with this statement: " For people with these variants, achieving real leanness is unlikely". It's difficult, but not impossible.

I'm surprised that there was no mention of Prader-Willi Syndrome, the PWS mouse model, or some of the unique variants in that patient population. There are some real answers to be found by talking with PWS parents.

Stephan Guyenet said...

Hi Laurie,

I don't think my statement implied that it's impossible, but it certainly would be much more difficult than for someone without one of these rare variants. These are serious mutations that throw a big wrench in the appetite control apparatus. Successfully losing weight with one of these mutations is not the same as a typical obese person losing weight (which is already difficult).

Prader-Willi is one of the "dysmorphic obesity syndromes" that I alluded to in a footnote on this post. It also results from a disturbance in appetite control mechanisms in the brain.

Unknown said...

This is probably too late for you but someone else may come along.

During this interview from a few years ago, Mary Enig says approximately 'information is coming out that trans-fats eaten by the mother during the second trimester is causing overweight/obese babies prone to being obese adults.'
That's not exact but the basic idea is correct.

As an adult.
I can eat low carb to stay even but need a constrained eating time to lose weight.
In my case some days 7 hours or less others as little as two worked.

Packaged food can work too, as long as I don't get hungry. (Some worked some not.)Casein works but I don't know about children.