12 ms·

A metabolic master switch underlying human obesity

131 points by apas 11y ago

jobu 11y ago
"The paper is a tour de force, according to Evan Rosen, a professor of medicine at Harvard Medical School who was not involved in the research." That's some pretty high praise. Also, it wasn't entirely clear to me if they're already testing this on humans. They mentioned using the CRISPR/Cas9 to manipulate genes in human cells, is that just donated human tissue?
- linuxguy2 11y ago
  From the article: "the researchers gathered adipose samples from healthy Europeans"
gwern 11y ago
The paper is: "FTO Obesity Variant Circuitry and Adipocyte Browning in Humans", Claussnitzer et al 2015; fulltext: http://www.nejm.org/doi/full/10.1056/NEJMoa1502214 http://www.nejm.org/doi/full/10.1056/NEJMoa1502214
- kybernetyk 11y ago
  So I checked my rs1421085 status and luckily I don't have the obesity variant. I guess the cause of my overweight is my laziness then :)
  - zrail 11y ago
    How did you do this?
    - kybernetyk 11y ago
      Got a 23andme analysis some time ago. Now I can just search for gene SNPs (those IDs that start with rs) in the data set and see what variants I have. It's pretty cool.
      - jauer 11y ago
        For the lazy, if you have 23andme and are signed in: https://www.23andme.com/you/explorer/snp/?snp_name=rs1421085 https://www.23andme.com/you/explorer/snp/?snp_name=rs1421085
        AndrewDucker 11y ago
        Thak you - turns out I have two Cs in there. Fascinating!
        deleted 11y ago
        [deleted]
        riemannzeta 11y ago
        Another thanks. Probably the most value I've gotten out of 23andme to date
        kybernetyk 11y ago
        Try out http://geneticgenie.org/methylation-analysis/ http://geneticgenie.org/methylation-analysis/ It might show you some genetic disorders. As it did for me which I then had confirmed by a doctor. Now I supplement a special form of Folic acid and my homocysteine blood levels are normal (they have been elevated for the last 30 years I guess, wich is not too good).
        BurningFrog 11y ago
        Thanks! You understand UI design! Not sure if I should be glad I'm not at risk or sad that I don't have that excuse.
  - tibbon 11y ago
    I looked up mine as well. I find it really amazing that we can just look these things up so easily now.
  - manmal 11y ago
    If I read this correctly, and I have genotype CC, then this would mean that I'm at risk, right?
    - bdevine 11y ago
      I'm completely unfamiliar with this stuff, but from the article: "In risk individuals, a thymine (T) is replaced by a cytosine (C) nucleobase, which disrupts repression of the control region and turns on IRX3 and IRX5. This then turns off thermogenesis, leading to lipid accumulation and ultimately obesity... Switching the C to a T in risk individuals turned off IRX3 and IRX5, restored thermogenesis to non-risk levels, and switched off lipid storage genes." So yes, CC is taken to mean "risk" and CT is likewise "non-risk". As always, one finding doesn't indicate ultimate truth, so take this all with a grain of salt (or not, depending on what 23andMe has to say about your sodium intake).
      - nether 11y ago
        So TT is lowest risk? That's what I have. I don't really gain weight...
        toomuchtodo 11y ago
        Damn it, I'm CC. "Switching the C to a T in risk individuals turned off IRX3 and IRX5, restored thermogenesis to non-risk levels, and switched off lipid storage genes." Hurry up CRISPR-CAS9. Need this fixed!
  - deleted 11y ago
    [deleted]
  - sowhatquestion 11y ago
    Mine is CT... does that entail a lower risk?
balabaster 11y ago
It would be interesting if they could find some food that flipped this on... clearly obesity is reaching epidemic proportions and there appears to be some correlation between this and the consumption of processed foods. It would be interesting to figure out if there's something in our food that is flipping the switch to lead down that path. Now that we have some (apparently) credible evidence correlating these switches with obesity, it would be handy to be able to see what to avoid to prevent this switch from being triggered... also if there's something that's not in control of the drug companies that we could eat to flip it back.
- kybernetyk 11y ago
  I don't know if you need a switch to flip the gene variant on/off when it comes to processed food. I lost 10kg since February by just not eating sugars anymore. I always assumed I wouldn't eat much sugar because I don't like sweets and I don't drink soda. But once I started counting added sugars in the processed foods I consumed it became clear I was consuming way too much of the stuff. Nowadays I just watch out to buy products with 0 sugar in it. Now that's of course no silver bullet but a pretty low hanging fruit when it comes to improving your overall health.
  - epalmer 11y ago
    I've given up all carbs except what is in nuts and fibrous vegetables. My appetite is greatly reduced and U feel better. (Keto adapted diet) 21 libs down in 7 weeks. Blood pressure down a lot. Swelling down, energy up. Feeling better. And yes I do exercise. Try to do 5 hours a week. Probably average 4.5 hrs / week. It is frustrating that processors add sugar to virtually everything.
- seiji 11y ago
  some food that flipped this on Stop eating bread (yes, pizza counts as bread. beer counts as bread. stop it). Stop drinking calories unless you're exercising for 2+ hours at once (yes, fruit juice is bad for you. stop it). The practice of making "processed foods" is essentially just cramming carbs and salt into everything and making it as highly concentrated as possible. Much processed food (read: basically anything pre-packaged in a wrapper) is more like a high calorie MRE food brick instead of something you should be combining with other foodstuffs. We know how food interacts with human bodies. Water doesn't cause fat growth. Dietary fat doesn't cause fat growth (the chemical 'fat' isn't human fat tissue, so drinking a gallon of olive oil won't increase your fat stores). High glycemic sugars cause fat growth in non-glycogen depleted bags of bones. Turns out we can stop getting obese just by not eating things causing obesity.
jug5 11y ago
Coca-cola?
deleted 11y ago
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deleted 11y ago
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- Anderkent 11y ago
  Of course. But for some reason some people stop being hungry when they eat enough to maintain weight, and some people are hungry unto obesity. Willpower is not an answer to obesity; it always breaks down when you starve. Finding out why it seems the hunger setpoint has recently moved up (and not only for humans!) is the real goal.
- TeMPOraL 11y ago
  I think the bigger danger is people accusing others of laziness. Making people miserable over a thing they probably have very little explicit control of may not be the best way to go. Yvain has a great post on the topic, I highly recommend it: http://lesswrong.com/lw/2as/diseased_thinking_dissolving_questions_about/ http://lesswrong.com/lw/2as/diseased_thinking_dissolving_que....
forrestthewoods 11y ago
I found the master switch. It's called self-responsibility.
- 746F7475 11y ago
  What if you were a fat kid. Other kids made fun of you and adults told you to "lose weight", but never gave you actual tips just "eat healthy and move more". How do you go about eating healthy as a 10 year old? You don't. You eat what your parents put on the table and if your parents are also fat there is going to be a lot of fatty foods and few healthy foods and the healthy foods will often taste horrible in comparison. How do you go about moving more? You could play outside, but who plays outside these days? You just spend your time playing video games and even if other kids are into sports ball you are fat and slow, and most likely to complain, so no one wants to play with you. Now imagine this goes on for ~20 years. You are now pushing 30, being overweight/obese your whole life. When people talk about weight they just tell you to "lose weight", but again without any solid steps just: "have self control and eat less and move more". Running is out of the question because of your bad knees, under your weight. Walking is fine as long as you take it slow and don't walk too long. So your gains are very minimal, you don't even sweat (expect from the Sun) since you can't go fast or long before your legs start to hurt. So people tell you it's all about food, so you try to lower your food intake. It's hell for a week, but somehow you manage it. You starve yourself for two months which feels like 5 years. You manage to lose weight, not that you know how much since no scale is big enough for you, but your pants start to sag. So you do what people around you want to do, you celebrate, because what's one night of having fun going to do, right? You got your new smaller pants and it's time to hit the town. Next thing you realize it's 6 weeks later, you are shoveling cake in your face at alarming rate and your pats are starting to look like skinny jeans. You feel like shit, and since you were a kid what have you been doing when you feel like shit? You grab a soda or a cupcake or something else that's bad for you. It's not just about having self-control, because you have life time of nagging about your weight on your back. People have always told you that you weren't good enough, that you should lose weight, but no one has taken the time and guide you on the right path. Losing weight is simple in theory, but hard in practice and it takes a lot of time and effort, more than most people are willing to dedicate.
untilHellbanned 11y ago
What I don't like is how the press and often scientists make every paper seem like something was newly identified. With no disrespect to the authors of this particular study, they didn't "unveil a new pathway". Several previous works over the past decade have honed in on this exact "master switch". E.g., Identification of FTO as relevant to obesity (2007): http://www.ncbi.nlm.nih.gov/pubmed/17434869 http://www.ncbi.nlm.nih.gov/pubmed/17434869 Connection of FTO and IRX3 (2014): http://www.ncbi.nlm.nih.gov/pubmed/?term=24646999 http://www.ncbi.nlm.nih.gov/pubmed/?term=24646999
linkydinkandyou 11y ago
Still, you can't make matter out of thin air, can you? At some point, it's all just overeating, isn't it? How can "metabolism" differences account for more than a few percent differences. Fat people don't have nuclear reactors in their stomachs creating energy -- they're eating too much. 60% of Americans didn't get fat because their "genetics" changed. I suppose some people may store excess food intake more readily as fat, and some may just poop it out, but the ultimate core is: you're eating TOO MUCH. I'm 5'10 and 160#. Maximum weight for me according to height/weight charts is 175. Every now and then I creep up to 170. I simply look at the BMR charts to see what my basic rate metabolism is, eat ~4500 calories less than that a week, and I lose a pound and a half a week. The math always works exactly. I do this every three or four years if I catch my weight creeping up and get back to 160. Fatties are gonna fat. We don't need more excuses for them, do we? They're causing us to spend billions of dollars on health care.
PaulHoule 11y ago
It is better to think of this as a target of intervention with drugs and other therapies than as a "gene therapy" product. The article says that the key process is enabling thermogenesis: "Follow-up experiments showed that IRX3 and IRX5 act as master controllers of a process known as thermogenesis, whereby adipocytes dissipate energy as heat, instead of storing it as fat. Thermogenesis can be triggered by exercise, diet, or exposure to cold, and occurs both in mitochondria-rich brown adipocytes that are developmentally related to muscle, and in beige adipocytes that are instead related to energy-storing white adipocytes." If you apply all the methods in terms of exercise, diet, and exposure to cold, you are pushing this switch the right way -- some people might need harder pushing than others.
s3nnyy 11y ago
> “Obesity has traditionally been seen as the result of an imbalance between the amount of food we eat and how much we exercise, but this view ignores the contribution of genetics to each individual’s metabolism” People might misunderstand this to justify laziness. I have an obese co-worker, who likes to eat several hundred grams of chocolate along with soft-drinks daily. He always quotes genetics to counterargument my elaborations on the first law of thermodynamics.
- ygjb 11y ago
  Yep, but knowing that smart researchers are finding more evidence for why people are overweight despite running and cycling regimes, and trying to maintain a relatively strict balance of nutrition sure makes my efforts feel a little less futile ;) You can't do much about people who are dishonest with themselves anyway.
- nevinera 11y ago
  People who have never struggled with their weight typically talk about obesity as if it is an uncomplicated phenomenon, an equation to follow, and pretend that cause and effect are obvious and easily discernible. If he is consuming ridiculous quantities and types of food, it probably means he has given up. Spend enough time carefully controlling your diet and producing minimal gains while the people around you don't seem to have to put any effort into maintaining their weights, and you will give up too. People are complicated and biology is complicated, and yet every thin person in the country thinks they can express The Fundamental Truth About Obesity in a single sentence. edit: I will reply to several responses here - your experience that 'losing weight is simple' is not a data point, it's an anecdote. Losing weight is simple for quite a few people. It's also astonishingly difficult for quite a few other people. Stop acting like your personal experience is strong scientific evidence for your point of view.
  - jpollock 11y ago
    Myself, I've got a choice. Either I'm at a constant weight and I'm stupid due to low blood sugar, or I end up gaining weight. It's incredibly hard for me to find the right balance, I haven't managed it yet.
rubicon33 11y ago
"By editing a single nucleotide position using the CRISPR/Cas9 system — a technology that allows researchers to make precise changes to a DNA sequence — the researchers could switch between lean and obese signatures in human pre-adipocytes." How far off are we from therapy using the CRISPR/Cas9 system? I would imagine that while it's easy to edit the sequence for cells in a petri dish, editting the cells of an entire organism (human) is not likely to happen in our lifetime?
- no_news_is 11y ago
  Radiolab had a story on it: http://www.radiolab.org/story/antibodies-part-1-crispr/ http://www.radiolab.org/story/antibodies-part-1-crispr/ As I recall: it works great, is super cheap (~ $80 per application?), and is pretty easy to use, they successfully used it on rats already and it seems like it should work on any type of organism.
- munificent 11y ago
  > I would imagine that while it's easy to edit the sequence for cells in a petri dish, editting the cells of an entire organism (human) is not likely to happen in our lifetime? We've been doing it experimentally for decades, though the technique is controversial. Recently, a few gene therapies have been approved for clinical use. https://en.wikipedia.org/wiki/Gene_therapy https://en.wikipedia.org/wiki/Gene_therapy
JamesBarney 11y ago
The phrase that being overweight is "simply calories in vs calories out" is both trivially true and completely unhelpful. It's similar to thinking we have solved poverty. People living in poverty should spend less and make more. Problem solved. The much more interesting questions are 1. Why does it take some people more food to reach the same level of satiety as others? 2. Why do some people's bodies burn off excess calories through things like non-exercise activity thermogenesis and other store it as fat? 3. Do different types of food effect long term satiety? By changing what we eat can we effect our weight in the long term? 4. How does the body increase hunger and turn off self-control when there is reduced food intake? The only known "solutions" we currently have to obesity are dieting and exercise. The problem is the long term efficacy rate of dieting is around 5%. If dieting were a drug it would never pass FDA approval for effectiveness. Exercise has only modest effects and is probably more effective as preventing weight gain than causing weight loss. We still have so much more to learn. We are just at the beginning of figuring out the causes and solutions to this issue.
- Almaviva 11y ago
  > The phrase that being overweight is "simply calories in vs calories out" is both trivially true and completely unhelpful. Why is it completely unhelpful? The corollary is that if you adjust your intake to X (where X might have to be determined empirically for the individual), and use planning and your conscious brain to know when and what to eat, you _will_ lose weight. This is a revelation to some people, who, once they realize the simplicity of it and plan around it, are able to completely change their bodies. Many of these same people try various intuitive plans that don't work for them (because they don't have the intuition) or try to manipulate exercise first (which makes some people increase appetite). If you don't believe me that it works, is useful, and is a revelation, go lurk on the myfitnesspal forums for a while or /progresspics on reddit and read how people succeed.
  - linkydinkandyou 11y ago
    Agreed! How hard is it _not_ to do something? If you eat less than your BMR, you will lose weight. Period. The fact that _maybe_ there are some people who can overeat and poop it out instead of storing it as fat is interesting, but so what. Obesity is the worst problem facing America right now, and we're all enablers.
nlh 11y ago
Thought exercise: Extend a finding like this out to the (il)logical conclusion 5, 10, 15 years out -- we figure out what causes the body to store fat, we develop the wonder drug that everyone's been waiting for that 'flips the switch' (even in otherwise healthy people), and suddenly everyone has 7.5% bodyfat and weighs exactly as much as they want to. And then....what? Well from a macro scale, I think some things get better -- overall population health goes up, obesity/fat-related diseases go down. But does heart disease? I wonder if it goes up -- if everyone looks like they've wanted by shutting off the body's fat stores, does the motivation to do cardio go down for some people? (Cardio has huge benefits for things way beyond your bodyfat, but that won't stop a big chunk of the population from giving up on it.) And from a purely superficial angle -- now everyone who wants one has a "ripped" body. But some guys are still bald, or have back hair, or or or. We'll still find a way to feel bad about ourselves, even with six-packs. Thoughts?
- gambiter 11y ago
  > And then....what? Well from a macro scale, I think some things get better -- overall population health goes up, obesity/fat-related diseases go down. But does heart disease? I wonder if it goes up -- if everyone looks like they've wanted by shutting off the body's fat stores, does the motivation to do cardio go down for some people? I don't understand the tendency some people have to find a negative in something that is mostly positive. It doesn't make sense to me. Sure, some negatives MIGHT happen, but are you really trying to justify not moving forward with this research because some people might use it as an excuse to be lazy? Really? What if everyone being the weight they want gives them more self-confidence, which gives them reason to get out more? What if there's less depression? What if there are fewer people with diabetes? There's potential to have some really great effects on the population at large here.
  - nlh 11y ago
    > are you really trying to justify not moving forward with this research because some people might use it as an excuse to be lazy? Really? No of course not! Hence my mention of 'thought exercise' -- I'm trying to spur discussion, get some other peoples' input, and explore an idea. My initial instinct was "awesome! health and low body fat for everyone!" I'm a perpetual optimist, but one of the most valuable skills I've learned as I've gotten older is the recognition that there's always _some_ con to the pro, and I think one of the valuable things about a community (and a discussion) is the exercise of looking at all sides of topic. (Which, btw, you've provided, even if unintentional ;)
grok2 11y ago
In this context, this report from 23andMe is interesting....perhaps old news: http://blog.23andme.com/wp-content/uploads/2015/03/5-N8XiOLkGIgydwX_SS-IQ_23-08_Genetic_Associations_With_Traits1.pdf http://blog.23andme.com/wp-content/uploads/2015/03/5-N8XiOLk...

131 points by apas 11y ago

jobu 11y ago

"The paper is a tour de force, according to Evan Rosen, a professor of medicine at Harvard Medical School who was not involved in the research." That's some pretty high praise. Also, it wasn't entirely clear to me if they're already testing this on humans. They mentioned using the CRISPR/Cas9 to manipulate genes in human cells, is that just donated human tissue?

linuxguy2 11y ago
From the article: "the researchers gathered adipose samples from healthy Europeans"

gwern 11y ago

The paper is: "FTO Obesity Variant Circuitry and Adipocyte Browning in Humans", Claussnitzer et al 2015; fulltext: http://www.nejm.org/doi/full/10.1056/NEJMoa1502214 http://www.nejm.org/doi/full/10.1056/NEJMoa1502214

kybernetyk 11y ago
So I checked my rs1421085 status and luckily I don't have the obesity variant. I guess the cause of my overweight is my laziness then :)
- zrail 11y ago
  How did you do this?
  - kybernetyk 11y ago
    Got a 23andme analysis some time ago. Now I can just search for gene SNPs (those IDs that start with rs) in the data set and see what variants I have. It's pretty cool.
    - jauer 11y ago
      For the lazy, if you have 23andme and are signed in: https://www.23andme.com/you/explorer/snp/?snp_name=rs1421085 https://www.23andme.com/you/explorer/snp/?snp_name=rs1421085
      - AndrewDucker 11y ago
        Thak you - turns out I have two Cs in there. Fascinating!
      - deleted 11y ago
        [deleted]
      - riemannzeta 11y ago
        Another thanks. Probably the most value I've gotten out of 23andme to date
        kybernetyk 11y ago
        Try out http://geneticgenie.org/methylation-analysis/ http://geneticgenie.org/methylation-analysis/ It might show you some genetic disorders. As it did for me which I then had confirmed by a doctor. Now I supplement a special form of Folic acid and my homocysteine blood levels are normal (they have been elevated for the last 30 years I guess, wich is not too good).
      - BurningFrog 11y ago
        Thanks! You understand UI design! Not sure if I should be glad I'm not at risk or sad that I don't have that excuse.
- tibbon 11y ago
  I looked up mine as well. I find it really amazing that we can just look these things up so easily now.
- manmal 11y ago
  If I read this correctly, and I have genotype CC, then this would mean that I'm at risk, right?
  - bdevine 11y ago
    I'm completely unfamiliar with this stuff, but from the article: "In risk individuals, a thymine (T) is replaced by a cytosine (C) nucleobase, which disrupts repression of the control region and turns on IRX3 and IRX5. This then turns off thermogenesis, leading to lipid accumulation and ultimately obesity... Switching the C to a T in risk individuals turned off IRX3 and IRX5, restored thermogenesis to non-risk levels, and switched off lipid storage genes." So yes, CC is taken to mean "risk" and CT is likewise "non-risk". As always, one finding doesn't indicate ultimate truth, so take this all with a grain of salt (or not, depending on what 23andMe has to say about your sodium intake).
    - nether 11y ago
      So TT is lowest risk? That's what I have. I don't really gain weight...
      - toomuchtodo 11y ago
        Damn it, I'm CC. "Switching the C to a T in risk individuals turned off IRX3 and IRX5, restored thermogenesis to non-risk levels, and switched off lipid storage genes." Hurry up CRISPR-CAS9. Need this fixed!
- deleted 11y ago
  [deleted]
- sowhatquestion 11y ago
  Mine is CT... does that entail a lower risk?

balabaster 11y ago

It would be interesting if they could find some food that flipped this on... clearly obesity is reaching epidemic proportions and there appears to be some correlation between this and the consumption of processed foods. It would be interesting to figure out if there's something in our food that is flipping the switch to lead down that path. Now that we have some (apparently) credible evidence correlating these switches with obesity, it would be handy to be able to see what to avoid to prevent this switch from being triggered... also if there's something that's not in control of the drug companies that we could eat to flip it back.

kybernetyk 11y ago
I don't know if you need a switch to flip the gene variant on/off when it comes to processed food. I lost 10kg since February by just not eating sugars anymore. I always assumed I wouldn't eat much sugar because I don't like sweets and I don't drink soda. But once I started counting added sugars in the processed foods I consumed it became clear I was consuming way too much of the stuff. Nowadays I just watch out to buy products with 0 sugar in it. Now that's of course no silver bullet but a pretty low hanging fruit when it comes to improving your overall health.
- epalmer 11y ago
  I've given up all carbs except what is in nuts and fibrous vegetables. My appetite is greatly reduced and U feel better. (Keto adapted diet) 21 libs down in 7 weeks. Blood pressure down a lot. Swelling down, energy up. Feeling better. And yes I do exercise. Try to do 5 hours a week. Probably average 4.5 hrs / week. It is frustrating that processors add sugar to virtually everything.
seiji 11y ago
some food that flipped this on Stop eating bread (yes, pizza counts as bread. beer counts as bread. stop it). Stop drinking calories unless you're exercising for 2+ hours at once (yes, fruit juice is bad for you. stop it). The practice of making "processed foods" is essentially just cramming carbs and salt into everything and making it as highly concentrated as possible. Much processed food (read: basically anything pre-packaged in a wrapper) is more like a high calorie MRE food brick instead of something you should be combining with other foodstuffs. We know how food interacts with human bodies. Water doesn't cause fat growth. Dietary fat doesn't cause fat growth (the chemical 'fat' isn't human fat tissue, so drinking a gallon of olive oil won't increase your fat stores). High glycemic sugars cause fat growth in non-glycogen depleted bags of bones. Turns out we can stop getting obese just by not eating things causing obesity.

jug5 11y ago

Coca-cola?

deleted 11y ago

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deleted 11y ago

[deleted]

Anderkent 11y ago
Of course. But for some reason some people stop being hungry when they eat enough to maintain weight, and some people are hungry unto obesity. Willpower is not an answer to obesity; it always breaks down when you starve. Finding out why it seems the hunger setpoint has recently moved up (and not only for humans!) is the real goal.
TeMPOraL 11y ago
I think the bigger danger is people accusing others of laziness. Making people miserable over a thing they probably have very little explicit control of may not be the best way to go. Yvain has a great post on the topic, I highly recommend it: http://lesswrong.com/lw/2as/diseased_thinking_dissolving_questions_about/ http://lesswrong.com/lw/2as/diseased_thinking_dissolving_que....

forrestthewoods 11y ago

I found the master switch. It's called self-responsibility.

746F7475 11y ago
What if you were a fat kid. Other kids made fun of you and adults told you to "lose weight", but never gave you actual tips just "eat healthy and move more". How do you go about eating healthy as a 10 year old? You don't. You eat what your parents put on the table and if your parents are also fat there is going to be a lot of fatty foods and few healthy foods and the healthy foods will often taste horrible in comparison. How do you go about moving more? You could play outside, but who plays outside these days? You just spend your time playing video games and even if other kids are into sports ball you are fat and slow, and most likely to complain, so no one wants to play with you. Now imagine this goes on for ~20 years. You are now pushing 30, being overweight/obese your whole life. When people talk about weight they just tell you to "lose weight", but again without any solid steps just: "have self control and eat less and move more". Running is out of the question because of your bad knees, under your weight. Walking is fine as long as you take it slow and don't walk too long. So your gains are very minimal, you don't even sweat (expect from the Sun) since you can't go fast or long before your legs start to hurt. So people tell you it's all about food, so you try to lower your food intake. It's hell for a week, but somehow you manage it. You starve yourself for two months which feels like 5 years. You manage to lose weight, not that you know how much since no scale is big enough for you, but your pants start to sag. So you do what people around you want to do, you celebrate, because what's one night of having fun going to do, right? You got your new smaller pants and it's time to hit the town. Next thing you realize it's 6 weeks later, you are shoveling cake in your face at alarming rate and your pats are starting to look like skinny jeans. You feel like shit, and since you were a kid what have you been doing when you feel like shit? You grab a soda or a cupcake or something else that's bad for you. It's not just about having self-control, because you have life time of nagging about your weight on your back. People have always told you that you weren't good enough, that you should lose weight, but no one has taken the time and guide you on the right path. Losing weight is simple in theory, but hard in practice and it takes a lot of time and effort, more than most people are willing to dedicate.

untilHellbanned 11y ago

What I don't like is how the press and often scientists make every paper seem like something was newly identified. With no disrespect to the authors of this particular study, they didn't "unveil a new pathway". Several previous works over the past decade have honed in on this exact "master switch". E.g., Identification of FTO as relevant to obesity (2007): http://www.ncbi.nlm.nih.gov/pubmed/17434869 http://www.ncbi.nlm.nih.gov/pubmed/17434869 Connection of FTO and IRX3 (2014): http://www.ncbi.nlm.nih.gov/pubmed/?term=24646999 http://www.ncbi.nlm.nih.gov/pubmed/?term=24646999

linkydinkandyou 11y ago

Still, you can't make matter out of thin air, can you? At some point, it's all just overeating, isn't it? How can "metabolism" differences account for more than a few percent differences. Fat people don't have nuclear reactors in their stomachs creating energy -- they're eating too much. 60% of Americans didn't get fat because their "genetics" changed. I suppose some people may store excess food intake more readily as fat, and some may just poop it out, but the ultimate core is: you're eating TOO MUCH. I'm 5'10 and 160#. Maximum weight for me according to height/weight charts is 175. Every now and then I creep up to 170. I simply look at the BMR charts to see what my basic rate metabolism is, eat ~4500 calories less than that a week, and I lose a pound and a half a week. The math always works exactly. I do this every three or four years if I catch my weight creeping up and get back to 160. Fatties are gonna fat. We don't need more excuses for them, do we? They're causing us to spend billions of dollars on health care.

PaulHoule 11y ago

It is better to think of this as a target of intervention with drugs and other therapies than as a "gene therapy" product. The article says that the key process is enabling thermogenesis: "Follow-up experiments showed that IRX3 and IRX5 act as master controllers of a process known as thermogenesis, whereby adipocytes dissipate energy as heat, instead of storing it as fat. Thermogenesis can be triggered by exercise, diet, or exposure to cold, and occurs both in mitochondria-rich brown adipocytes that are developmentally related to muscle, and in beige adipocytes that are instead related to energy-storing white adipocytes." If you apply all the methods in terms of exercise, diet, and exposure to cold, you are pushing this switch the right way -- some people might need harder pushing than others.

s3nnyy 11y ago

> “Obesity has traditionally been seen as the result of an imbalance between the amount of food we eat and how much we exercise, but this view ignores the contribution of genetics to each individual’s metabolism” People might misunderstand this to justify laziness. I have an obese co-worker, who likes to eat several hundred grams of chocolate along with soft-drinks daily. He always quotes genetics to counterargument my elaborations on the first law of thermodynamics.

ygjb 11y ago
Yep, but knowing that smart researchers are finding more evidence for why people are overweight despite running and cycling regimes, and trying to maintain a relatively strict balance of nutrition sure makes my efforts feel a little less futile ;) You can't do much about people who are dishonest with themselves anyway.
nevinera 11y ago
People who have never struggled with their weight typically talk about obesity as if it is an uncomplicated phenomenon, an equation to follow, and pretend that cause and effect are obvious and easily discernible. If he is consuming ridiculous quantities and types of food, it probably means he has given up. Spend enough time carefully controlling your diet and producing minimal gains while the people around you don't seem to have to put any effort into maintaining their weights, and you will give up too. People are complicated and biology is complicated, and yet every thin person in the country thinks they can express The Fundamental Truth About Obesity in a single sentence. edit: I will reply to several responses here - your experience that 'losing weight is simple' is not a data point, it's an anecdote. Losing weight is simple for quite a few people. It's also astonishingly difficult for quite a few other people. Stop acting like your personal experience is strong scientific evidence for your point of view.
- jpollock 11y ago
  Myself, I've got a choice. Either I'm at a constant weight and I'm stupid due to low blood sugar, or I end up gaining weight. It's incredibly hard for me to find the right balance, I haven't managed it yet.

rubicon33 11y ago

"By editing a single nucleotide position using the CRISPR/Cas9 system — a technology that allows researchers to make precise changes to a DNA sequence — the researchers could switch between lean and obese signatures in human pre-adipocytes." How far off are we from therapy using the CRISPR/Cas9 system? I would imagine that while it's easy to edit the sequence for cells in a petri dish, editting the cells of an entire organism (human) is not likely to happen in our lifetime?

no_news_is 11y ago
Radiolab had a story on it: http://www.radiolab.org/story/antibodies-part-1-crispr/ http://www.radiolab.org/story/antibodies-part-1-crispr/ As I recall: it works great, is super cheap (~ $80 per application?), and is pretty easy to use, they successfully used it on rats already and it seems like it should work on any type of organism.
munificent 11y ago
> I would imagine that while it's easy to edit the sequence for cells in a petri dish, editting the cells of an entire organism (human) is not likely to happen in our lifetime? We've been doing it experimentally for decades, though the technique is controversial. Recently, a few gene therapies have been approved for clinical use. https://en.wikipedia.org/wiki/Gene_therapy https://en.wikipedia.org/wiki/Gene_therapy

JamesBarney 11y ago

The phrase that being overweight is "simply calories in vs calories out" is both trivially true and completely unhelpful. It's similar to thinking we have solved poverty. People living in poverty should spend less and make more. Problem solved. The much more interesting questions are 1. Why does it take some people more food to reach the same level of satiety as others? 2. Why do some people's bodies burn off excess calories through things like non-exercise activity thermogenesis and other store it as fat? 3. Do different types of food effect long term satiety? By changing what we eat can we effect our weight in the long term? 4. How does the body increase hunger and turn off self-control when there is reduced food intake? The only known "solutions" we currently have to obesity are dieting and exercise. The problem is the long term efficacy rate of dieting is around 5%. If dieting were a drug it would never pass FDA approval for effectiveness. Exercise has only modest effects and is probably more effective as preventing weight gain than causing weight loss. We still have so much more to learn. We are just at the beginning of figuring out the causes and solutions to this issue.

Almaviva 11y ago
> The phrase that being overweight is "simply calories in vs calories out" is both trivially true and completely unhelpful. Why is it completely unhelpful? The corollary is that if you adjust your intake to X (where X might have to be determined empirically for the individual), and use planning and your conscious brain to know when and what to eat, you _will_ lose weight. This is a revelation to some people, who, once they realize the simplicity of it and plan around it, are able to completely change their bodies. Many of these same people try various intuitive plans that don't work for them (because they don't have the intuition) or try to manipulate exercise first (which makes some people increase appetite). If you don't believe me that it works, is useful, and is a revelation, go lurk on the myfitnesspal forums for a while or /progresspics on reddit and read how people succeed.
- linkydinkandyou 11y ago
  Agreed! How hard is it _not_ to do something? If you eat less than your BMR, you will lose weight. Period. The fact that _maybe_ there are some people who can overeat and poop it out instead of storing it as fat is interesting, but so what. Obesity is the worst problem facing America right now, and we're all enablers.

nlh 11y ago

Thought exercise: Extend a finding like this out to the (il)logical conclusion 5, 10, 15 years out -- we figure out what causes the body to store fat, we develop the wonder drug that everyone's been waiting for that 'flips the switch' (even in otherwise healthy people), and suddenly everyone has 7.5% bodyfat and weighs exactly as much as they want to. And then....what? Well from a macro scale, I think some things get better -- overall population health goes up, obesity/fat-related diseases go down. But does heart disease? I wonder if it goes up -- if everyone looks like they've wanted by shutting off the body's fat stores, does the motivation to do cardio go down for some people? (Cardio has huge benefits for things way beyond your bodyfat, but that won't stop a big chunk of the population from giving up on it.) And from a purely superficial angle -- now everyone who wants one has a "ripped" body. But some guys are still bald, or have back hair, or or or. We'll still find a way to feel bad about ourselves, even with six-packs. Thoughts?

gambiter 11y ago
> And then....what? Well from a macro scale, I think some things get better -- overall population health goes up, obesity/fat-related diseases go down. But does heart disease? I wonder if it goes up -- if everyone looks like they've wanted by shutting off the body's fat stores, does the motivation to do cardio go down for some people? I don't understand the tendency some people have to find a negative in something that is mostly positive. It doesn't make sense to me. Sure, some negatives MIGHT happen, but are you really trying to justify not moving forward with this research because some people might use it as an excuse to be lazy? Really? What if everyone being the weight they want gives them more self-confidence, which gives them reason to get out more? What if there's less depression? What if there are fewer people with diabetes? There's potential to have some really great effects on the population at large here.
- nlh 11y ago
  > are you really trying to justify not moving forward with this research because some people might use it as an excuse to be lazy? Really? No of course not! Hence my mention of 'thought exercise' -- I'm trying to spur discussion, get some other peoples' input, and explore an idea. My initial instinct was "awesome! health and low body fat for everyone!" I'm a perpetual optimist, but one of the most valuable skills I've learned as I've gotten older is the recognition that there's always _some_ con to the pro, and I think one of the valuable things about a community (and a discussion) is the exercise of looking at all sides of topic. (Which, btw, you've provided, even if unintentional ;)

grok2 11y ago

In this context, this report from 23andMe is interesting....perhaps old news: http://blog.23andme.com/wp-content/uploads/2015/03/5-N8XiOLkGIgydwX_SS-IQ_23-08_Genetic_Associations_With_Traits1.pdf http://blog.23andme.com/wp-content/uploads/2015/03/5-N8XiOLk...