
A metabolic master switch underlying human obesity - apas
https://news.mit.edu/2015/pathway-controls-metabolism-underlying-obesity-0819
======
JamesBarney
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
> 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.

~~~
JPKab
The reason that it isn't helpful, despite you're peer reviewed, laboratory
evidence cited on MyFitnessPal postings, is that the causal mechanism that
common sense derives from this is completely incorrect.

People aren't fat because they eat too much. People (and mammals) eat too much
because their fat cells are being metabolically triggered by environmental
and/or genetic factors to store fat at a higher than normal rate, diverting
calories from operational needs, thus stimulating hunger.

Bears don't go into hibernation because they've gotten fat. They get fat
because their endocrine system begins gearing up for hibernation, and telling
their fat cells to kick into overdrive growing. They will literally burn
muscle while simultaneously gaining fat in this stage, like all hibernating
mammals. The other side effect of growing fat cells is massive hunger,
obviously.

In humans, simple things like not eating sugar can help correct the endocrine
factors which, for a lot of people, cause the fat cells to do this. However,
genetic factors are going to be a different story.

I say this as somebody who is fit and active, but have had running buddies who
are fat. Pitting will-power against metabotically driven hunger ends, in the
long-term, with biology winning every time.

Without endocrine/genetic factors taken into account, reduction in calories in
simply causes a mammalian body's system to reduce calories out by making the
subject less energetic.

~~~
the8472
> thus stimulating hunger.

Then go hungry every now and then once you know the causal link. It's not like
it's an irresistible force to which you have no choice but to succumb.

> Pitting will-power against metabotically driven hunger ends, in the long-
> term, with biology winning every time.

In my experience [sample size: 1] it's entirely possible to ignore hunger for
quite some time.

Additionally there are options such as adding filler ingredients that help
with reaching satiety with fewer calories. Carbohydrates with a low glycemic
index which get absorbed more slowly, thus avoiding a boom-bust cycle as far
as your blood sugar levels are concerned are also something you can adjust.
This also helps staving off the next hunger for more hours.

It's certainly not an inevitable "I'm hungry, therefore I must eat and grow
fat" link that can't be broken.

~~~
JeremyNT
There are also plenty of factors which can lead to overeating which are not
caused by the hunger response (i.e. craving food based on learned behaviors,
peer pressure, desire for a particular taste, boredom, depression, etc).

The grandparent's post seems highly suspect to me. Hunger no doubt plays a
_role_ in obesity among some individuals, but the ultimate determinant is how
many calories are available to be processed versus how many are expended,
regardless of _why_ they have been ingested.

~~~
DanBC
When you take a hypothetical individual and lock them in a room and control
their food you can give them a restricted calorie diet and they will lose
weight.

No-one credible denies that.

What the people arguing against CICO are saying is that it's fucking stupid
pointless advice to give to a population because while true it's not helpful.
We know it's not helpful because we've been saying loud and clear it for many
years and obesity rates have risen in almost every country every year.

"We could cure cancer if we just kill all the cancer cells" is true but not
helpful.

"We could fix world hunger if hungry people just grew food" is true but not
helpful.

~~~
JeremyNT
I'm going to quote the grandparent here:

> People aren't fat because they eat too much. People (and mammals) eat too
> much because their fat cells are being metabolically triggered by
> environmental and/or genetic factors to store fat at a higher than normal
> rate, diverting calories from operational needs, thus stimulating hunger.

Is hunger really the primary cause of overeating for those who suffer from
obesity? This seems unlikely to me.

It's true that calin/calout is a simplification, but there are _many_ who
outright deny it. They may not be credible to _you_ , but they are still
powerful voices across all media and their gospel is happily accepted by many.

> What the people arguing against CICO are saying is that it's fucking stupid
> pointless advice to give to a population because while true it's not
> helpful. We know it's not helpful because we've been saying loud and clear
> it for many years and obesity rates have risen in almost every country every
> year.

Posts like yours that deride calin/calout as a useless oversimplification miss
the mark; of _course_ it's a very basic fact, not a treatment plan. It's
crucial that people _understand_ that this is the mechanism at play if they
want to succeed at regulating their weight, and despite your assertion that
"nobody credible denies it" there are a lot of big names who will sell you all
kinds of solutions that ignore it, and focus on specific distractions rather
than looking at obesity as a complex disease with many causes that lead to
calorie surplus.

------
gwern
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
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 :)

~~~
manmal
If I read this correctly, and I have genotype CC, then this would mean that
I'm at risk, right?

~~~
bdevine
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
So TT is lowest risk? That's what I have. I don't really gain weight...

~~~
toomuchtodo
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!

------
balabaster
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.

~~~
RIMR
>there appears to be some correlation between this and the consumption of
processed foods.

Really? I would love a source on this, because it seems that the #1 reason is
that the average portion size has increased greatly in the past 30 years while
people are exercising less and less.

It would be great if we could find a way to "flip a switch" to make weight-
loss easier, but it's downright foolish to pretend that we are gaining weight
for any other reason than that we are eating too much and exercising too
little.

This "processed foods make you fat" nonsense is infuriating because it just
validates people's beliefs that their weight problems have nothing to do with
their personal habits, instead placing the blame on the quality of the foods
they've been eating.

~~~
_delirium
There's a moderate amount of evidence that the type of food plays a
significant role in overconsumption of calories. One factor is differing
satiation for the same number of calories, i.e. 300 calories of some foods
make you feel fuller than 300 calories of other foods. There is also something
specifically weird going on with a handful of foods that seem to promote
ongoing consumption to degrees seen much less often with other kinds of food.
Soda and salty/fat snacks are two where people are observed consuming _huge_
numbers of calories in kind of a chain-consumption binge, which is much less
often seen with, say, pork chops or broccoli.

~~~
RIMR
>One factor is differing satiation for the same number of calories

>a handful of foods that seem to promote ongoing consumption

>people are observed consuming huge numbers of calories in kind of a chain-
consumption binge

As I said: It has absolutely nothing to do with the foods or how they are
processed; it has everything to do with how much people eat of these foods.

Fatty/Salty foods can promote overconsumption, but blaming the foods for a
person's lack of self-control is, as I said previously, incredibly foolish.

Sure, food trends may have increased the amount of fatty/salty foods on the
market in the past 30 years, and this certainly would contribute to the
obesity epidemic. However, the burden ultimately rests on the consumer to
ensure that they are not only consuming healthy foods, but that they are
consuming healthy portions of these foods compared to the amount of exercise
they get daily.

I could easily eat 3 Big Macs for lunch, but I am aware that that would be
1600+ calories, so I don't.

~~~
balabaster
> As I said: It has absolutely nothing to do with the foods or how they are
> processed; it has everything to do with how much people eat of these foods.
> > Fatty/Salty foods can promote overconsumption, but blaming the foods for a
> person's lack of self-control is, as I said previously, incredibly foolish.

Not everyone has the same self-control/discipline. Exploitation of this fact
by food companies is becoming more visible as time goes on. One that
immediately springs to mind are the slogans for products such as Pringles:
"Once you pop, you can't stop!"

Certain foods cater to, nay exploit, addiction and human behavioral traits.
You can't exploit weaknesses in the human psyche and then say "it's their own
fault," without assuming any responsibility or blame.

That's like blaming a drug addict entirely for becoming addicted to crack and
not apportioning any of the blame to the dealer... not everything is entirely
the fault of the... I'm struggling for a better word than victim, but that's
not really the word I mean. Most addicts are at first desensitized, then
conditioned and then coerced into trying what they become addicted to long
before they become addicted.

Food companies have been slated to add chemicals into their food that have
been found to correlate with addiction, to keep people coming back for their
product. The media desensitizes, conditions and coerces people into trying
their product. Portions are decided not based on what is a scientifically
proportionate amount of food, but what is most profitable or will make the
"client" keep coming back for more - to feed the addiction - in exactly the
same way that dealers cut their drugs with chemicals that feed addiction and
keep the addict coming back for more - even though many of them want
desperately to quit.

~~~
yellowapple
> Food companies have been slated to add chemicals into their food that have
> been found to correlate with addiction, to keep people coming back for their
> product.

What does this even mean? Barring the more obvious "correlation != causation"
issue here, this seems... logically fuzzy at best, and also reeks a bit of the
"chemicals are bad" fad. Do you happen to have examples of such chemicals that
"have been found [by whom?] to correlate [how strongly?] with addiction [to
themselves? to something else? to what?]"?

------
PaulHoule
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.

------
nlh
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
> 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
> 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 ;)

~~~
gambiter
Heh, apologies for being reactionary in my comment. Seems like we're on the
same page then. :)

------
rubicon33
"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
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.

------
s3nnyy
> “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.

~~~
nevinera
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
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.

~~~
ashark
My body's response to caloric restriction defies the math behind all the
weight loss calculators I've seen. I don't even know how it's physically
possible. Which sucks, because I find it fairly easy to limit my calorie
intake, but have to eat at nearly concentration-camp levels to drop weight,
which isn't fun.

However, my body responds _very_ well to exercise, especially strength
training. Less convenient (takes time, space, maybe some equipment) but,
conversely, works _way better_ for me than any tables/calculators I've seen
say it should. You might try that, if you haven't.

------
jobu
_" 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
From the article: "the researchers gathered adipose samples from healthy
Europeans"

------
untilHellbanned
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)

------
grok2
In this context, this report from 23andMe is interesting....perhaps old news:
[http://blog.23andme.com/wp-
content/uploads/2015/03/5-N8XiOLk...](http://blog.23andme.com/wp-
content/uploads/2015/03/5-N8XiOLkGIgydwX_SS-
IQ_23-08_Genetic_Associations_With_Traits1.pdf)

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

~~~
746F7475
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.

~~~
forrestthewoods
No matter what you are responsible for your body. Period. Full stop. I am not
responsible for your body. As an adult your parents are not responsible for
your body. The government is not responsible for your body. You and you alone
are responsible.

Your body may be more susceptible to holding onto fat than the average person.
You may have genetic markers that makes you more likely to over indulge. There
are one of a million factors that may make you more likely to be overweight.
But literally none of them change the fact that you and you alone are
responsible for your body.

~~~
746F7475
It's easy to say that, since it is true after all, but you are not helping in
this matter at all. You are not going to get a single fatty to lose a pound of
weight by telling them: "hey! it's your fault!". Fatties know that, but that
doesn't mean it will in any way make them change what they are doing.

~~~
forrestthewoods
Constantly searching for genetic markers as excuses doesn't help either. It's
not your fault! Your genetics cause you to over eat and hold on to all of the
fat! And you know what that changes? Nothing. Literally nothing. You can shift
blame to genetics or make excuses on how your parents didn't teach you how to
eat healthy but it doesn't matter. At the end of day one and only one person
holds the keys of responsibility.

~~~
746F7475
I never said anything even remotely about genetics.

And I never blamed my parents, they did what they thought was best, but I dare
to suggest that adults constantly telling kids: "you should lose weight" for
years doesn't do any good. At worst you start to resent everyone who says that
and then you are in deep trouble.

If you have been skinny to normal weight your whole life you have no idea how
hard it is to keep up with a diet and how easily it gets out of hand. Kids are
the place where we should start treating this epidemic and it doesn't start
with nagging them every time they visit a doctor/nurse. It starts with proper
school meals which favor salads instead of shit like pasta, rice and potatoes,
and removing shit like coke machines from school property. With PE classes
where kids actually get exercise and isn't just about playing few rounds of
sports ball. And some actual advice with weight problems and proper after
school activities (these probably should be sports ball activities) which
don't cost a lot.

Maybe I'm way off base here. Maybe I'm just crazy. But I know what my
educational system is like and for most part it ain't helping.

~~~
JoeAltmaier
Some changes happening. Here in Iowa, our high school has a fitness loft, and
PE is about everything you say. Cardio, weights, running, inclusive activities
and good sportsmanship all play a part. My boys are lean and mean, in no small
part because of their high school experiences!

