[[link removed]]

OZEMPIC IS A BRAIN DRUG  
[[link removed]]


 

Sarah Zhang
March 5, 2024
The Atlantic
[[link removed]]


*
[[link removed]]
*
[[link removed]]
*
*
[[link removed]]

_ The latest weight loss drugs succeeded not because we fully
understood the hormone they’re based on but because we got lucky.
And drug development, for all the careful research required, does
sometimes come down to luck. _

Ozempic, focal5 (CC BY-NC 2.0)

 

When scientists first created the class of drugs that includes
Ozempic, they told a tidy story about how the medications would work:
The gut releases a hormone called GLP-1 that signals you’re full, so
a drug that mimics GLP-1 could do the exact same thing, helping people
eat less and lose weight.

The rest, as they say, is history. The GLP-1 revolution birthed
semaglutide, which became Ozempic and Wegovy, and tirzepatide, which
became Mounjaro and Zepbound—blockbuster drugs that are rapidly
changing the face of obesity medicine. The drugs work as intended: as
powerful modulators of appetite. But at the same time that they have
become massive successes, the original science that underpinned their
development has fallen apart. The fact that they worked was
“serendipity,” Randy Seeley, an obesity researcher at the
University of Michigan, told me. (Seeley has also consulted for and
received research funding from companies that make GLP-1 drugs.)

Now scientists are beginning to understand why. In recent years,
studies have shown that GLP-1 from the gut breaks down quickly and has
little effect on our appetites. But the hormone and its receptors are
naturally present in many parts of the brain
[[link removed]] too. These
brain receptors are likely the reason the GLP-1 drugs can curb the
desire to eat—but also, anecdotally, curb other desires
[[link removed]] as
well. The weight-loss drugs are ultimately drugs for the brain.

Obesity medications differ in a key way from the natural molecule
they’re meant to mimic: They last a lot longer. GLP-1 released in
the gut has a half-life of just minutes in the bloodstream, whereas
semaglutide and tirzepatide have half-lives measured in days. This is
by design. Both drugs were specifically engineered to resist
degradation, so that they need to be injected only once a week.
(The very first GLP-1 drug
[[link removed]] on
the market, exenatide, had to be injected twice a day
[[link removed]] when it was released, in
2005—the field has come a long way.) The medications are also given
at levels much higher than natural GLP-1 ever reaches in the
bloodstream; Seeley tends to put it at five times as high, but he said
even that may be a gross underestimate.

Read: Ozempic makes you lose more than fat
[[link removed]]

By indiscriminately flooding the body with long-lasting molecules, the
injections likely allow engineered GLP-1 drugs to penetrate parts of
the body that the natural gut hormone cannot—namely, deep in the
brain. First-generation GLP-1 drugs including exenatide, which are far
less powerful than the current crop, have been shown to cross the
blood-brain barrier and tickle areas important for appetite and
nausea. Exactly what Ozempic and its successors
[[link removed]] do
is still less clear, but they are so effective that many scientists
think they must be reaching far, directly or indirectly.

All of this matters because the brain, as we now know, has its own
GLP-1 system, parallel to and largely separate from whatever is going
on in the gut. Neurons in the hindbrain, sitting at the base of the
skull, secrete their own GLP-1
[[link removed]], while
receptors listening to them are found throughout the brain. In animal
experiments, hitting those receptors indeed suppresses appetite.

It took a long time for scientists to appreciate the extent of GLP-1
in the brain, Karolina Skibicka, a neuroscientist at Penn State, told
me. When she published her first study
[[link removed]], in
2012, on a GLP-1 drug’s impact on the dopamine reward system, she
had to spend two years going back and forth with skeptical reviewers.
At the time, she said, “the idea was considered so wild.”
(Skibicka has received research funding from the Novo Nordisk
Foundation, which has a majority ownership in but whose grants are
commercially independent from Novo Nordisk, the manufacturer of
Ozempic.) Since then, in a series of clever experiments using rodents,
scientists have been able to show that GLP-1 drugs likely act on the
brain. They don’t seem to work, for example, to suppress appetite in
mice whose brain GLP-1 receptors have been genetically erased
[[link removed]]. Moreover, the
effects of GLP-1 extend beyond food
[[link removed]]: Rodents given the drugs
will drink less alcohol and use less cocaine. Anecdotally, too, people
on GLP-1 medications have reported spontaneously quitting drinking,
smoking, shopping, and other addictive and compulsive behaviors.

Read: Did scientists accidentally invent an anti-addiction drug?
[[link removed]]

A more refined understanding of how GLP-1 works in the brain could
help improve the current injections. Nausea and vomiting
[[link removed]] are among the
most common side effects and would seem to go hand in hand with a lack
of appetite. But these symptoms appear to be governed by distinct
systems in the brain, Scott Kanoski, a neuroscientist at the
University of Southern California, told me. In fact, scientists have
been able to find brain areas in rodents where GLP-1 analogues can
suppress appetite without causing nausea, which hints at the
possibility of developing drugs that do the same.

Even as scientists zero in on the likely mechanisms of these
weight-loss drugs, they are encountering new and baffling questions.
Tirzepatide, for example, activates receptors for a second hormone
called GIP, and this is often cited as a potential explanation
[[link removed]] for
its slightly superior efficacy over semaglutide, which acts on GLP-1
alone. But just last month, Amgen released data
[[link removed]] on
a new drug that activates GLP-1 receptors, _blocks_ GIP receptors,
and still helps people lose weight. How can two drugs with opposite
actions on GIP have the same outcome?

Scientists are perplexed, but they are not shocked. For years and
years, promising findings in rats and mice did not translate into
real-world treatments for obesity. Drugs based on other, seemingly
important hormones—ghrelin (the “hunger hormone”) and leptin
(the “satiety hormone”)—were never able to achieve
[[link removed]] the
spectacular clinical results of GLP-1. The latest drugs succeeded not
because we fully understood the hormone they’re based on but because
we got lucky. And drug development, for all the careful research
required, does sometimes come down to luck.

In the end, gut GLP-1 could still be important—just not for appetite
regulation. The stuff that is produced by the gut, specifically in the
end of the small intestine and the colon, makes up most of the GLP-1
produced in the body, Daniel Drucker, an endocrinologist at Mount
Sinai Hospital in Toronto, told me. It also tends to spike during gut
infections. Drucker now thinks that GLP-1 in the gut is primarily
responsible for controlling inflammation. (He has consulted for and
received research funding from companies making GLP-1 drugs.) Other
scientists have explored using GLP-1 drugs to treat inflammatory gut
disease
[[link removed](21)00259-5.pdf],
such as ulcerative colitis and Crohn’s. But they’ve run into a bit
of a dilemma: Many people with these conditions are already
underweight, and GLP-1 drugs are just too good at making people lose
more weight.

_Sarah Zhang [[link removed]] is a
staff writer at The Atlantic._

_Never miss a story from The Atlantic. Subscribe for in-depth
reporting and analysis.
[[link removed]]_

* Science
[[link removed]]
* health
[[link removed]]
* Obesity
[[link removed]]

*
[[link removed]]
*
[[link removed]]
*
*
[[link removed]]

 

 

 

INTERPRET THE WORLD AND CHANGE IT

 

 

Submit via web
[[link removed]]

Submit via email
Frequently asked questions
[[link removed]]
Manage subscription
[[link removed]]
Visit xxxxxx.org
[[link removed]]

Twitter [[link removed]]

Facebook [[link removed]]

 




[link removed]

To unsubscribe, click the following link:
[link removed]