Wednesday, May 21, 2014

A New Understanding of an Old "Obesity Gene"

As you know if you've been following this blog for a while, obesity risk has a strong genetic component.  Genome-wide association studies (GWAS) attempt to identify the specific locations of genetic differences (single-nucleotide polymorphisms or SNPs) that are associated with a particular trait.  In the case of obesity, GWAS studies have had limited success in identifying obesity-associated genes.  However, one cluster of SNPs consistently show up at the top of the list in these studies: those that are near the gene FTO.

As with many of the genes in our genome, different people carry different versions of FTO.  People with two copies of the "fat" version of the FTO SNPs average about 7 pounds (3 kg) heavier than people with two copies of the "thin" version, and they also tend to eat more calories (1, 2).  

Despite being the most consistent hit in these genetic studies, FTO has remained a mystery.  As with most obesity-associated genes, it's expressed in the brain and it seems to respond somewhat to nutritional status.  Yet its function is difficult to reconcile with a role in weight regulation: 
  • It's an enzyme that removes methyl groups from RNA, which doesn't immediately suggest a weight-specific function.
  • It's not primarily expressed in the brain or in body fat, but in all tissues.
  • Most importantly, as far as we know, the different versions of the gene do not result in different tissue levels of FTO, or different activity of the FTO enzyme, so it's hard to understand how they would impact anything at all.  
An important thing to keep in mind is that GWAS studies don't usually pinpoint specific genes.  Typically, they tell us that obesity risk is associated with variability in a particular region of the genome.  If the region corresponds to the location of a single gene, it's a pretty good guess that the gene is the culprit.  However, that's not always the case...

A New Understanding of the FTO SNP

A paper recently published in Nature upturns everything we thought we knew about the FTO SNPs (3).  Dr. Scott Smemo and colleagues begin by pointing out that the FTO SNPs are associated with a non-coding region of the FTO gene.  What this means is that the SNPs are in a region of the gene that gets edited out prior to the construction of the FTO protein.  Non-coding regions don't contribute to the sequence of proteins such as FTO, but they do often contain regulatory elements that influence how the gene is expressed, or how it's spliced.

Usually, regulatory elements affect the expression of the closest gene, but sometimes they can act at quite a distance.  In the case of the FTO SNPs, Smemo and colleagues showed that they're associated with the expression of a gene called IRX3 that's located millions of base pairs away from it!  While the SNPs have no association with FTO expression, they are associated with IRX3 expression levels in the brain.  People with the "fat" SNPs have a higher level of IRX3 expression.

As I never tire of repeating, if you find a gene that impacts body fatness, the first place to look for its function is the hypothalamus.  The hypothalamus is the part of the brain that regulates body fatness, and most genes that affect body fatness have been linked to hypothalamic function in one way or another.

In this case, all signs were pointing to the brain as the key location of IRX3's effects.  To test this hypothesis, Smemo and colleagues made genetically modified mice that lack IRX3.  What they found is striking: IRX3 knockout mice are unusually lean, and totally resistant to dietary obesity.  While normal mice doubled their fat mass when fed a fattening diet, IRX3 knockout mice didn't gain a significant amount of fat on the same regimen.  They further reported that specifically interfering with IRX3 function in the hypothalamus also resulted in leanness, supporting the hypothesis that IRX3 exerts its weight-regulating function primarily in the hypothalamus.

What does IRX3 do?  It's a transcription factor, meaning it's a protein that regulates the expression of other genes.  It's known to be highly expressed in the brain and to play a role in brain development.  We can only speculate for the time being, but it may impact the development of brain circuits that regulate body fatness.  Or it may do something else-- no one knows.

The identification of IRX3 as the target of the FTO SNPs is really exciting because it suggests there's still a lot to be learned about how the brain regulates body fatness.  


OldTech said...

So what does this study mean for 'calorie in calorie out' or were the IRX3 knockout mice eating less?

Josh said...

OldTech, maybe it means that the mice ate the same but absorbed less or burnt more calories by generating more heat. Many people often forget while there's one way to get the calories in, there're many ways to get them out.

Stephan Guyenet said...

Hi OldTech,

They were apparently leaner due to higher energy expenditure, not lower food intake. There are a number of rodent models in which changes in energy expenditure rather than calorie intake gives them an atypical level of body fatness.

I don't know what it means for 'calories in, calories out' because I don't understand what the phrase 'calories in, calories out' means anymore. People use it to mean different things. If you define what you mean, I can give you an answer.

Hi Josh,

Well said.

JørgenS said...

That's a great discovery! I'm curious about the mechanism for how the mutations affect IRX3 expression. Since this is now a hot topic maybe lot's more about IRX3 will be published in the years to come. Thanks for reporting!

karl said...

I think looking for single cause gene effects, while they can be enlightening at times, is mostly going to disappoint. The problem is a philosophical assumption that our bodies are understandable as if they were designed.

While evolution is well accepted on the surface level of biology, most researchers assume that they will find things that are 'designed'. There is a huge difference between something that was evolved rather than engineered.

The reuse of proteins in non logical ways is the rule rather than the exception.

Imagine the automobile - if it's construction was evolved rather than, we might have the exact same part serving for the steering-wheel, flywheel, and rims.

When we look at control loops in the human body, we find multitudes of overlapping - inter nested loops.

This is because of the survival of single point mutations. To understand biology, one has to stop thinking like an engineer. I don't think we will find a single easily understandable control loop.

The brain obviously has a role, but I think it very unlikely that there are not other compensating loops that also have overlapping effects.

The result of this is that improvements in managing obesity is likely to come from practice (bottom up) rather than the top down - only then will the theories be fit to what works.

Anonymous said...

Hi Josh,

Excellent point as Stephan noted. :0 )

There certainly are many ways to use and/or waste energy. Energy can be led to many different pathways.

(Alex Filippenko has an excellent video explaining the conservation of energy in great detail with props included. Google "Alex Filippenko Thermodynamics." He comes in right after Michio Kaku. Filippenko is a genuine genius and his detailed work was a major factor in the discovery of Dark Matter and Dark Energy).

"The total amount of energy in a system can be neither created, nor destroyed. The matter and energy can change forms and they can turn into one another. But, the total amount of energy remains the same."

- Professor Alex Filippenko

Here is a neat tidbit: Regarding the conservation of energy, it is certainly valid for all of life- humans and animals etc. Hurricanes, lasers and Bernard cells are also part of the non - equilibrium dissipative thermodynamic system classification , although much less complex than humans. This area of thermodynamics ( open, non-equilibrium) is hellishly complicated. Humans exchange energy and matter with the environment. When we simply breathe we are changing the numbers of atoms and molecules in out body. Humans poop out energy. We also produce very substantial amounts of dissipated heat
(more wasted energy) - up to 80 to 123 watts.

The chemical energy we ingested changed forms. Some is wasted as heat, some wasted by excretion, , some is used for various bodily maintenance, for energy etc. The human body derives its energy from the chemical energy contained in the chemical bonds of the food we digest and converts it into heat and kinetic energy.

How energy is used is a major factor, as scientists told me. But, yes, energy balance is an extremely important factor- but is not the only thing going on.The creation of fat cells is a regulated process and can be powerfully influenced by genes. Some people are naturally fatter than others. It is their biology. Physicists themselves (specializing in non - equilibrium thermodynamics) told me that while the first alw is valid for all of life, obesity is a complex physiological /biochemical matter and not basic thermodynamics.

Everything else being equal, if one sat around all day and really kind of overate, they would be probe to likely gaining mass- most of it probably fat.

Physics is often taught wrong and presented to the public inaccurately. As some of us know, physics is not done by "fiat." There is a specific reason energy is conserved. The reason is this: As best we know the laws of physics are the same in this room as in that room. The fact that the laws of nature are the same here as there is responsible for something called "conservation of momentum." The laws of physics do not change over time as far as we can tell. Emmy Noether showed us that IF the laws of physics do not change over time there must be a QUANTITY that is conserved. We call that quantity "energy"- which is conserved.

So, the fact that energy is conserved in nature is a mathematical consequence of the fact that the laws of nature do not change over time.

P.S. Another thing not taught correctly is the speed of light topic. As far as we know nothing can travel THROUGH space faster than the speed of light. However, SPACE ITSELF can do whatever it wants and could exceed light speed. The universe is predicted to eventually be expanding faster than light. Sorry to go too much off topic with the light thingy.

I just thought I would share this. :)

Best wishes,