Chapter 2: Hacking
the hunger system with GLP-1
So we think of eating and hunger as being a
very straightforward thing. “Oh yeah, if you’re a little hungry, I eat
something, now I don’t want to eat anymore” but it’s really complicated and it
involves a lot of continual dialogue between the body and the mind using both
the senses that are pointed out at the world and the senses that are pointed
inward at the body. So, if you can imagine walking down the street in New York
City near little hungry and you smell some pizza, “That smells good” and the
first thing you’re doing is you’re making a decision – am I hungry? Do I want
to go seek out where this odor is coming from? “Oh yes, I do,” so you’re using
interceptive information to say yes my stomach is not distended and full of
nutrients and I feel hunger, it’s been a while since I last ate so I’m
interested in this idea. You’re using your memory to say “Oh yes, I remember
that I like pizza. That’s a food that I enjoy” and so these smells are bringing
up positive associations and that is influencing your decision to go seek it
out. And then let’s say you order a slice and you have it in your hand and
you’re looking at it and you’re seeing it so you’re taking in information with
your eyes you’re smelling it and then you’re making a decision, “Do I want to
put this in my mouth or not?” and if it smells a little off if you sniff it and
you think it might have spoiled or the oil is rancid or something bad, you’re
gonna say “Well no, maybe I won’t put that in my mouth after all.” But really,
eating this a series of decisions. So now let’s say you’ve taken a bite and you
go “Oh, that’s delicious, yes I’m tasting the salt, I’m tasting the fat, I get
that nice yeasty thing from the crust, there’s also mouth feel in my mouth, I’m
I gonna swallow this bite” and you’re saying “Oh yes this is palatable food,
there’s nothing wrong with it and so I won’t spit it out, I’ll swallow it” –
that’s yet another decision.
And then you’re going on eating your slice
perhaps you’re walking down the street and you have to make a decision “Am I
getting full? This slice is enormous. Am I gonna finish it or am I gonna chuck
some of it in the trash and leave it be?” And that decision uses several
different streams of information coming from your body. It’s using fast neural
signals from your stomach that are saying how distended is my stomach? How much
has it swollen as a result of food filling it up? And it is also using fast
information from the stomach there cells in the lining of the stomach that
evaluate the nutrient content of the food. This is why you can’t just drink a
lot of water, for example, distended your stomach and then suppress your
appetite that doesn’t work as a diet strategy. Your stomach knows what’s
inside. It can tell the difference between water and food and it can even tell
what kind of food is there – is it fatty? Is it proteinaceous? Is it carbs?
That sort of information saying “Oh yes there are proteins there, there are
fats there, there’s a fairly high level of them” and these are signals that go
rapidly to your brain and inform the decision “Should I terminate this meal and
stop eating? Or should I should I keep going a little while longer?”
And then say 20 minutes later, when you are
making a decision do I want to eat again, there are yet other sensors in not
your stomach but in the first part of your small intestine that are evaluating
the nutrient content of the food as it passes there and saying you know “I just
ate, I have plenty of nutrients. I have a feeling of fullness. I’m not going to
eat again for a while.” How does that happen? Well that is a slow hormonal
signal and when food is sensed by particular neurons in the lining of the small
intestine, they secrete a hormone and the hormone is called glucagon-like peptide-1
(or glp-1) and this hormone has several effects. It acts on receptors in the
stomach to slow gastric motility, so your stomach empties less quickly, but
more importantly it goes to centers in your brain that control your appetite
and they suppress your appetite for tens of minutes or an hour or two
afterwards.
So we all know that if you put sweet food in
your mouth it tastes sweet and that the reason for that is that on your tongue
and in your oral cavity there are special sensors for sugars, but what most
people don’t know is that there are similar sensors for sugars actually in your
stomach and in your small intestines and those sensors send information to your
brain to guide decisions like should I stop eating food right now.
Curiously though while artificial sweeteners
that are widely used and sodas and other foods, they do a very good job of
mimicking real sugar for the sweet sensors that are in your oral cavity, they
don’t fool the sensors that are in your stomach and your intestines because
those in sensors are molecularly different. So what that means is when you eat
artificial sweeteners there’s a mismatch. Your mouth is telling you “Oh this is
sugar!” But your gut is saying “No, I don’t think so, this isn’t real sugar”
and as a consequence your brain is getting conflicting signals and this is
probably some of the reason why artificial sweeteners are really not a very
effective strategy for losing weight.
GLP-1 and the new era of appetite control
If you haven’t been living under a rock for
the last few years, you’ve heard that there are very popular diet drugs that
are based upon the hormone GLP-1. Now, GLP-1 is a class of molecule called a
peptide – it’s a short bit of a protein – and these peptides are broken
down very quickly in your bloodstream so when your small intestine secretes GLP-1,
that signal is only acting on your brain very briefly and so you would need to
inject many times a day and it it’s not wouldn’t be an effective drug. But some
clever chemists at the drug company Novo Nordisk realized that you could take the natural GLP-1 molecule
and hang chemical groups off the side, in particular you could hang fatty acids
off the side, and these fatty acids cause this GLP-1 like molecule then to bind
to a protein in the blood called albumin. And when it’s bound to
albumin, it’s much more resistant to being degraded by enzymes, and it’s much
more resistant to being immediately excreted by the kidney.
As a result, while natural GLP-1 acts for only
minutes, this modified
GLP-1 that makes a GLP-1 based drug can suppress appetite for a very very long
time. It can live for a long time in the bloodstream and as a
consequence, you can use it to make a drug that you inject once a week and
suppresses appetite strongly. I’m talking about things like semaglutide, which is known as Wegovy or
Ozempic, or Tirzepatide,
which is known as Zepbound or Mounjaro, and these drugs by mimicking this natural signal
are very effective at suppressing appetite and people are losing
typically between 12 and 17 percent of their body weight after taking a once a
week injection of these drugs over many weeks.
But, they seem to be even better than that. In
other words, if you compare the health benefits that you can measure from
people who are taking GLP-1 drugs, it seems that there are beneficial effects
above and beyond what you would predict from just the amount of weight they’re
losing. And we don’t entirely know why this happens, but it makes sense
biologically because the receptor for the hormone GLP-1 which is also going to
be activated by these drugs, it’s not just in your stomach and it’s not just in
your brain, it’s in all kinds of organs. It’s in your heart, it’s in your
kidneys, it’s in your liver, it’s in all kinds of places, and it’s doing
something good there. We
don’t entirely know what that is, but it’s probably some sort of
anti-inflammatory effect that provides benefit beyond just what the weight loss
is doing.
GLP-1 based weight loss drugs aren’t perfect.
They have a lot of benefits, but they have some side effects. Some people feel nauseated, some people
feel gastrointestinal distress, sometimes people feel brain fog or a loss of
energy on them. And the newer generations of weight loss drugs that are
being developed right now may help to make those side effects better.
The other thing is that when you eat less, you
don’t just lose fat mass, you also lose muscle mass, so you got to be really
careful if you’re losing weight on a GLP-1 drug. You want to go to the gym and
do load bearing exercise to keep your muscle mass up, you want to make sure
that you’re consuming enough protein to allow your muscles to be able to
continue to stay at a reasonable size, so some of these problems may only
emerge when we see people using them for years and years and years. And you have to use them for
years and years and years because they only work as long as you consume them.
You go on a GLP-1 drug, you use it for a year, you go off the drug – you’re gonna gain all the weight
back. It doesn’t seem to have a permanent reversal effect.
When these drugs were first developed if you
would ask to me as a neuroscientist would these drugs that suppress appetite
also suppress the other kinds of rewards that people tend to overdo, like
alcohol or drugs of abuse, or even compulsive shopping or gambling – all of
which activate the brain’s reward circuitry – I would have guessed no.
I would have said there’s gonna be a separate
circuit for appetite and there are reasons to keep that apart from the general
reward circuitry. But the indications are that this is not entirely the case.
So, it’s early days, but there are promising indications that the GLP-1 based weight loss drugs have some
effectiveness for helping people to control their alcohol consumption and to
help them get off of psychoactive drugs, and maybe even to deal with compulsive
behaviors that are making problems in their life, like compulsive shopping or
compulsive gambling. It’s gonna be really interesting to see how this
plays out in research in the next few years.
So there are some really interesting things
that have come out in the last few years in body-to-brain signaling that have
implications for weight loss. One of them has to do with exercise. we know that
when you exercise intensively it stimulates appetite and so some people think
“Well, you know I might go to the gym and work out real hard, but then I’m
gonna be a real hungry and then I’m gonna eat a lot of food, and maybe there
won’t be a net benefit.”
It seems to be though, that intensive exercise
does have a net benefit. The amount that it stimulates your appetite doesn’t
entirely compensate for the amount of weight that you burn through the
intensive exercise.
Why is that? Well part of it seems to be that
when you have very intensive exercise you produce a metabolite called lactate.
It becomes conjugated in your body with an amino acid called phenylalanine and
this conjugated compound seems to act through a rather complicated biochemical
cascade in the body to get to the brain to suppress appetite itself. So,
intensive exercise really does seem to be a good thing to do.
Very few people can lose all the weight they
want to lose from intensive exercise itself, but it is very, definitely, a
benefit, and of course it has myriad benefits well beyond weight loss and
looking good. It has benefits for your mood, it has benefits for maintaining
your cognitive function as you age, there’s all kinds of great reasons to want
to exercise intensively, but weight loss is one of them.
