How Opposite Approaches to Weight Loss Can Both Work

Good Morning.

Scientists studying a receptor involved in appetite have been trying to explain a biological puzzle.

Some weight-loss drugs activate it.

Others block it.

Strangely, both approaches can work.

The receptor, known as GIPR, is one of several targets behind the new generation of obesity medications. Drugs such as Mounjaro and Zepbound activate it, while other treatments under development take the opposite approach and inhibit it. If one strategy helps reduce weight, researchers wanted to know, why would doing the reverse produce a similar result?

A new study from the University of Cambridge suggests the answer may depend on where in the brain the receptor is being targeted.

In experiments with mice, researchers found that activating GIPR primarily affected the brainstem, an area involved in appetite and nausea. There, activation reduced food intake and body weight.

Blocking the receptor worked through a different route.

In the hypothalamus, which helps regulate hunger and body weight, GIPR appears to act partly as a brake on signals telling the brain that the body has had enough to eat. Blocking the receptor removed some of that restraint, allowing fullness signals to become stronger.

In other words, two drugs can act in opposite ways on the same biological target and still arrive at a similar outcome because they're influencing different brain circuits.

The finding may eventually matter for more than explaining an oddity of weight-loss medicine. Researchers found that targeting these pathways in combination with certain GLP-1 drugs could enhance their effects. It could help scientists design treatments that produce greater weight loss with fewer side effects, although the current research was conducted in mice and much remains to be tested in people.

It also adds another piece to our changing understanding of obesity treatment.

The gut and pancreas are important players. But increasingly, some of the most consequential action appears to be happening higher up.

Inside the circuits of the brain that decide when we've had enough.

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Longevity

The Long Game
One small thing for a longer life

Did You Know

A daily serving of leafy greens is tied to a brain that acts about 11 years younger.

Researchers followed 960 older adults for nearly five years and found that those who ate roughly one serving of leafy greens a day, such as spinach, kale, collards, or a leafy salad, had far slower memory and thinking decline than those who ate almost none. The difference worked out to about 11 years of brain aging. Nutrients like folate, lutein, and vitamin K may help explain why.

Nutrition is one of the six factors that shape how well we age. The Worthyest Longevity Index measures all six in 4 minutes. Yours, personalized. Get my score →

Source: Morris et al., Neurology, 2018 (Rush Memory and Aging Project, 960 adults, ~5 years; roughly one daily serving of leafy greens associated with slower cognitive decline, equivalent to ~11 years younger).

The Curiosity Edit

Today’s Insight: Medical Innovation

New Radiation-Free Lung Scan Can Spot Disease Sooner in Children, And it’s Much Safe

A new MRI technique is giving doctors a different way to see inside children’s lungs, including signs of disease that other tests can miss, without repeated exposure to radiation. Read the full story here.

Modern Living:

Brain & Mental Health

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Health & Wellness

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The Conscious Plate:

Food, Nutrition & Elevated Living

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This New Heart Health Review Might Change the Way You Order Your Coffee
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28 Best Lunch Box Snacks Approved by Moms, Dietitians and Kids
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Final Note

This is what we leave you with. A thought to end the day, carry in your pocket, or come back to later. Nothing big. Just something to reflect on.

When Ambition Opens Up

At first, ambition can feel like a ladder. There are obvious next steps, visible markers of progress, and people a few rungs ahead showing you where to go.

Then you begin to notice that not everyone is climbing the same thing.

Some people build careers around work they love. Others build work around a life they love. Some want influence, some independence, some enough money to stop thinking about money. Others discover that the thing they spent years chasing was never the thing they valued most.

That realization can change ambition without diminishing it.

You can still want more for yourself while becoming much more particular about what “more” means.

There isn't one good life waiting at the top.

There are many good lives, and ambition becomes more useful when you know which one you're trying to build.

Visit our website for more.

Pass It On

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