Wednesday, October 20, 2010

Obesity and the Brain

Nature Genetics just published a paper that caught my interest (1). Investigators reviewed the studies that have attempted to determine associations between genetic variants and common obesity (as judged by body mass index or BMI). In other words, they looked for "genes" that are suspected to make people fat.

There are a number of gene variants that associate with an increased or decreased risk of obesity. These fall into two categories: rare single-gene mutations that cause dramatic obesity, and common variants that are estimated to have a very small impact on body fatness. The former category cannot account for common obesity because it is far too rare, and the latter probably cannot account for it either because it has too little impact*. Genetics can't explain the fact that there were half as many obese people in the US 40 years ago. Here's a wise quote from the obesity researcher Dr. David L. Katz, quoted from an interview about the study (2):
Let us by all means study our genes, and their associations with our various shapes and sizes... But let's not let it distract us from the fact that our genes have not changed to account for the modern advent of epidemic obesity -- our environments and lifestyles have.
Exactly. So I don't usually pay much attention to "obesity genes", although I do think genetics contributes to how a body reacts to an unnatural diet/lifestyle. However, the first part of his statement is important too. Studying these types of associations can give us insights into the biological mechanisms of obesity when we ask the question "what do these genes do?" The processes these genes participate in should be the same processes that are most important in regulating fat mass.

So, what do the genes do? Of those that have a known function, nearly all of them act in the brain, and most act in known body fat regulation circuits in the hypothalamus (a brain region). The brain is the master regulator of body fat mass. It's also the master regulator of nearly all large-scale homeostatic systems in the body, including the endocrine (hormone) system. Now you know why I study the neurobiology of obesity.


* The authors estimated that "together, the 32 confirmed BMI loci explained 1.45% of the inter-individual variation in BMI." In other words, even if you were unlucky enough to inherit the 'fat' version of all 32 genes, which is exceedingly unlikely, you would only have a slightly higher risk of obesity than the general population.

30 comments:

JadeGordon said...

Recently there's been a lot of talk about the brain, addiction and food. Something about it doesn't sit right with me, I feel like there's something missing between how the brain deals with food, and traits of "addiction", and how the brain deals with addiction to substances not at all needed for survival.

I love your blog because I am not a scientist, but you explain things in such a way that helps me understand and learn. I would love it if this is relevant to your research in some way that you might like to expand on.

E.E. said...

This is not associated with this post, but I thought it might be of interest. Did you catch this article?

http://www.nytimes.com/2010/10/19/science/19bread.html?ref=science

I think it's interesting how they try to say this might be proof that there is little basis in the Paleo Diet. It's starchy vegetables that they were using for bread! Not gluten containing grains!

Fredrik Gyllensten said...

Great post Stephan. It confirmed my thought that, in almost all cases, blaiming geneticts for beinf fat is BULLSHIT.

Fredrik Gyllensten said...

That being said, there is to me no doubt that some people have an easier time staying lean then others, and that genes probably play some role there.

Kathryn Grace said...

Thank you. Forty years ago our diets did not consist of highly processed foods containing numerous ingredients derived in one way or another from only two food crops, corn and soy. Today, most diets do. I would be interested in seeing more studies that compare the diets of forty, fifty and even seventy years ago with the fast-food, highly processed food diets of today, and how those correlate with obesity.

ItsTheWooo2 said...

Genes control all of our potential. Environment has an effect only in so much that it activates certain genes, shuts off others.
It cannot be argued that only a small percentage of the population becomes substantially obese (i.e. more than 50 pounds overweight) yet we are all exposed to the same environment. This clearly must be a genetic difference, why one person fattens in an environment that the majority of other people do not.

If someone tells me that my history of being 160 pounds heavier than I am now with PCOS and reactive hypoglycemia is not at all genetic, I would think that person was a fool.
Of course it is not genetic in the sense of my eye color - but it is genetic in the sense that I have this tendency and must eat a special diet and take supplements and do a lot of things so as to prevent it from happening.
I have a long family history of fertility disorder and weight problems. My mother had no signs of PCOS (hyperandrogenism) but she did have irregular periods and she was very overweight. Her mother had the same irregular periods and mild weight problems, and HER mother also had the same issues. I am the only one so far out of 4 generations that has clinical PCOS and my obesity has been the most severe (although now it is controlled), but then again I was born in the 80s and I was exposed to an environment none of my mothers were. The environment (lots and lots of sugar and starch) can explain why my problems were so severe, but the tendency for fertility disorder and weight problems have always been there, it is genetic, innate.

Steven, we must focus on the genes because there are certainly many people - for example, yourself - who never gain much weight or only gain a couple of pounds even when they allow themselves to drink soda and eat cakes and candy. The difference between my family and your family and many other people's family is that my family has to eat low carb or else, whereas other people do not have to eat low carb or care too much about sugar and starch as the consequences are as mild as gaining maybe 10 or 15 pounds and feeling tired.

Jenny said...

What's missing here it the fact that exposure to chemical toxins can damage genes that were normal by inheritance.

That kind of genetic damage affecting babies in the womb probably has a lot to do with the skyrocketing incidence of toddler obesity and diabetes. It was long known that you cannot make a normal toddler overeat. Children of two or three haven't lived long enough to acquire obesity-caused diabetes.

DogwoodTree05 said...

Jenny,

On one of your posts about enviromental toxin damage as a cause of diabetes, I asked about the China paradox. Diabetes rates are rising swiftly in China, and while obesity is on the rise, there are still very few heavy people in China. Nearly every young adult and child I knew was normal to slender, and middle-aged Chinese were a bit thick around the middle, there were no people so large that they could not walk unassisted. The heavist Chinese I ever saw would be mildly obese by US standards. Koreans and Japanese, too, live mostly in polluted urban environments, yet their obesity rate of 3% is the lowest in the OECD. Not doubting that environmental toxins can damage genes related to metabolism, just wondering why obesity remains so much higher in the US compared to some other industrialized nations.

DogwoodTree05 said...

correction: "...and WHILE middle-aged Chinese were a bit thick around the middle,..."

ItsTheWooo2 said...

Jenny -
While I don't disagree with your idea that toxins may be damaging genes, you are missing important information about physiology when you use toddler obesity as a sign of toxin damage. It is known that metabolic disorder does not just affect the mother, but it programs the child for obesity as well. When rats are exposed to high leptin at birth (which is ubiquitous with high insulin and obesity , note), those rats are programmed for obesity from birth.

The reason each generation is fatter than the last generation is because successive prenatal exposure to high insulin, high glucose, and high leptin is programming us for obesity and diabetes. So a 50 pound overweight mother with mild high insulin during pregnancy has a 75 pound overweight daughter who has full blown gestational diabetes while pregnant, who has a 100 pound overweight daughter who has non-gestational diabetes at 35 years old, on and on. The prenatal exposure to the massively screwed up endocrine and metabolic systems of our mothers are setting children up for metabolic disorder and obesity at earlier ages, and more severe manifestations in adulthood.

Pregnancy exacerbates any underlying metabolic disorder, and the fetus is set up for an even more severe manifestation as the mother.

The originally triggering factor is probably primarily sugar and extreme calorie dense carbohydrate, but each generation is more metabolically damaged than the last as mothers are increasingly severely obese and diabetic with soaring insulin and glucose and leptin levels.

Jamison said...

Here's some fuel for the fire:

http://www.ncbi.nlm.nih.gov/pubmed/3941707

"An adoption study of human obesity.

We examined the contributions of genetic factors and the family environment to human fatness in a sample of 540 adult Danish adoptees who were selected from a population of 3580 and divided into four weight classes: thin, median weight, overweight, and obese. There was a strong relation between the weight class of the adoptees and the body-mass index of their biologic parents - for the mothers, P less than 0.0001; for the fathers, P less than 0.02. There was no relation between the weight class of the adoptees and the body-mass index of their adoptive parents. Cumulative distributions of the body-mass index of parents showed similar results; there was a strong relation between the body-mass index of biologic parents and adoptee weight class and no relation between the index of adoptive parents and adoptee weight class. Furthermore, the relation between biologic parents and adoptees was not confined to the obesity weight class, but was present across the whole range of body fatness - from very thin to very fat. We conclude that genetic influences have an important role in determining human fatness in adults, whereas the family environment alone has no apparent effect."

I think as always, is a mix of nature vs nurture. Could probably related to genes as well as a poor diet during pregnancy or it could be a recessive trait that only response to a trigger, such as the alcoholism-addiction genes that only express their harm in an environment where there is access to alcohol.

As a biased rule of thumb though, there is a strong correlation between people who use the word "toxins" and people who believe in irrational conspiracies. Lets not forget how much useless junk DNA we have such as the remnants of an ancient bovine virus. Moo.

lightcan said...

I think it might be useful to clarify at this point what does one mean by 'genetic'.
Itsthewoo, you might be referring to epigenetic changes when you talk about the history of a family or about how prenatal exposure to a unnatural, unhealthy diet damages the child. That's what Stephen was talking about, propensity to respond to an unnatural diet. And to me, 'we are all exposed to the same environment' sounds like a sweeping generalisation.

lightcan said...

Let's not blame the mothers only:
Dad's Weight and Diet Linked to Offspring's Risk of Diabetes
http://www.sciencedaily.com/releases/2010/10/101021103121.htm?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+sciencedaily+%28ScienceDaily%3A+Latest+Science+News%29

JBG said...

Jamison's comment about the Danish study is very interesting. But I'm wondering whether the complete(!) lack of influence of family environment might be an artifact of restricted range. Denmark is a small, relatively homogeneous country with a strong emphasis on social and economic equality. I find it difficult to believe that no effect would have been seen if some of the adoptees had grown up on SAD.

Anand Srivastava said...

@ItsTheWooo2

I think Epigenetics become more important than genetics within a couple of generations. Epigenetics concerns with the gene switches which get turned on and off based on the environment.

Our genes are created from the mother's side when she was born. While from Fathers side they are created when we are born. So the genes on/off state will depend somewhat on how healthy our maternal grandmother and maternal grandfather were and what they were eating, and there environment.

It will depend on our Fathers how healthy they are (the base genetic switches), what they ate and their environment.

Then we are nourished in our wombs, so we will get the some of our genes turned on/off based on what our mothers ate during the pregnancy, and her environment.

After being born the genes are still flip/flopping as we grow up.

I think the creation of the egg and the sperm provides the major base state. Then we are more likely to change during the birth and during the first two years of birth. Those two years will decide the strength of our internal organs and digestive system. How susceptible are they to the external agents.

So people are going to be affected more easily by the diet if they got bad genetic state (different from bad genes).

Finally there is the randomness of the whole process, some body might just be lucky to get the best genes from both the parents, and become lucky enough to be healthy.

But the chances go down every generation. So a child born to fat parents is more likely to be fat child compared to other children. Ofcourse he is also going to get the same diet that caused the obesity in the first place for the parents.

I think blaming genetics doesn't help.

Robert Andrew Brown said...

Anand

I agree with you as to the potential impact of epigenetic.

Do we know if the gene switches (expression) as against the genes themselves are zeroed at the point of conception. I attended a lecture which I did not fully understand where the lecturer suggested they were.

IF they are that would make us entirely dependent on the environmental influences in the womb to set our gene switches, which would make sense in term of preparing us for the environment in which we were to be born.

Anand Srivastava said...

Robert
I am not sure about the switches being reset to zero. That would depend on how the switches actually work.

I am not a biochemist, I have learnt everything on these sites.

From the article from Stephan, it looks like the genes themselves cause very little obesity. It also makes sense because our basic genes should not have altered too much since the last 200,000 years. There is very little genetic difference between humans.

But we do see a lot of genetic similarity in the way obesity or diseases affect us. Much of this could be explained by diet, but I somehow think there is more to it than just the diet.

There was a paper discussed by Stephan where Refined vegetable oils were causing multi-generational obesity in rats. This paper showed that somehow the diet of parent rats was affecting the baby rats over multiple generations. This can't be explained by genetics. But it could be explained by epigenetics assuming that we allow it to be carried over as traits from parents.

"Guppy" Honaker said...

I do agree that our brain has a big influence on our behavior - especially with a chemical imbalance in play. But I also think our attitude has a big influence on our brain and how we choose to deal with life, our health, and our eating habits.

- David

Aloe Vera Juice Benefits
Holistic Nutrition and Health

marshall said...

In the absence of a study investigating children adopted into grain, legume, and dairy-free hunter gatherer societies, I think we have to look a little deeper into the genetic basis for obesity.

Leptin gets thrown around as indicator of propensity for obesity. And this blog has speculated that leptin resistance may be induced by the consumption of neolithic foods. This has not been studied on humans and is pure speculation at this point.

Leptin resistance has been linked to obesity. Leptin in individuals has also been shown to have genetic correlation to the parents.

Maybe what is happening is that some individuals are more susceptible to leptin resistance due to an intolerance or sensitivity to neolithic and processed foods. Might that explain why the Pima, African American, and Latino populations have skyrocketing rates of diabetes, obesity, and heart disease. Or perhaps leptin resistance is more severe in certain populations that haven't traditionally consumed large amounts of grains and sugars.

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MsCFaith said...

This means if you're gaining a lot of abnormal weight, it could affect a part of your brain.

Natural way to wellness

Anand Srivastava said...

Robert,

Found a paper showing that epigenetics traits are forwarded over generations. They are not reset at birth.

http://www.pnas.org/content/103/46/17071.full

SWWBO said...

I was reading the other day about the increased use of female hormones throughout the US and the UK - creams that women apply are affecting their pets - spayed dogs and cats are going into "heat" due to the hormonal creams that their owners have on their hands or arms when petting them. The husbands and children of these women are developing breasts until the cream usage is stopped or used under better circumstances.

Also, in the past 40 years or so, birth control pills have been used by a huge percentage of women. I have read that a lot of these hormones are actually in water supplies in many cities -

This is just a hunch on my part, but couldn't the exposure to female hormones be causing some of the obesity? I do know those hormones definitely change one's metabolism, and weight gain is a common side-effect.

Tim Butterfield said...

I wonder whether the brain can change its management of fat over time. For example, when I was younger (before 20), I could eat anything and remain skinny. I was also fairly active, on my feet a lot and walking a lot. At 20, I got married, started eating richer foods (wife is a good cook), took time shortcuts (driving from one end of the mall to the other instead of walking), spent more time at a desk and less on my feet. All of these changes resulted in my gaining roughly 100 pounds over the years since (until last year). I've since started to lose some of that by becoming more active again. But, it's much harder to take off than it went on.

Back to my original wonderment. Was it just my activity level and calorie change that did this or did something change in my brain or genes as well? After being obese for a while, though I didn't start that way, why is it so much harder to take off than it went on? Did my genes change so I am now programmed to hold weight? Is my post gain state now similar to those who are obese and not active to begin with as I was? Just some more questions to ponder on this subject...

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daphne sy said...

I never thought of that. . great editorial and explanation! You help me understand that I never thought it's happening. For me, It's like smoking. You only smoke because your brain tell you so. Same as food=(
my blog, healthy flat

Dr. John Mitchell said...

all of you who think genes control us, think again:

-Genes are not self-emergent
-They just don't turn on without something in the environment telling them to turn on.
-They are covered in a protein coat in the cell nucleus
-They cannot simply open this coat and start making proteins

The concept of "gene-controlled-behavior" is an excuse for poor lifestyle choice...poor food choices and poor exercise habits.

Robert Andrew Brown said...

Anand

Thanks for the link.

I need to read it carefully (-:

You make a good point; at the simplest level if everything is reset there would be no epigenetic effect.

Very probably I did not fully understand the implication or limit of wider relevance of what was being explained in the lecture.

More reading required - when I have time (-:

Thanks

checkdent said...

I've heard of some more studies linking obesity to specific genes. But that as a fact doesn't help the personal problem of obesity. We all know the theory very well exercise daily, eat less, eat quality food. But in order to start doing that we need a motivation, and I think family and friends play a large part in this.

www.checkdent.com

Mike W said...

@John Mitchell
Given the Pima Indians were perfectly healthy prior to colonisation, but with the introduction of white flour and sugar suddenly en masse developed the highest rates obesity, type 2 diabetes and other related illnesses in the Western world within 2 generations, wouldn't it a be a fair to suggest that genes play a *big* role in the body's reaction to these foods? The longer they've been consumed within a population, the lesser their impact?