After 30 Years Fighting Obesity, This Researcher Finally Cracked It. Now He’s Working on a Version You Only Take Once

The scientist behind Mounjaro and Zepbound just revealed what comes next, and it involves five hormone signals in a single drug.

In a recent podcast interview, Professor Matthias Tschöp traced three decades of discovery, from obese lab mice to blockbuster medications.

His newest designs promise stronger results with fewer side effects.

Muscle loss, microdosing, and motivation also came up.

One twist about how these drugs actually work may surprise even seasoned health readers.

The Quintuple Agonist: What Comes After Retatrutide

Tschöp expects retatrutide, a triple agonist, to be approved around the end of this year or next. He describes weight loss near 30%, with no added side effects.

That puts a weekly injection on par with gastric bypass. His team did not stop there.

Well, we didn’t stop. We continued and published a few months ago a Nature paper on a quintuple agonist.

This design pairs GIP and GLP-1 with a triple PPAR agonist. Peptides ferry small-molecule payloads into targeted cells, like a Trojan horse.

Tschöp envisions personalized metabolic medicine, hitting select organs while also tackling inflammation and calorie burning.

• 2009: first glucagon/GLP-1 dual agonist published
• Next step: GIP/GLP-1 dual agonist, the basis for tirzepatide
• 2015: triple agonist published, now known as retatrutide
• Today: quintuple agonist reported in Nature

A GLP-1-Free Drug With No Nausea?

Nausea, vomiting, diarrhea, and constipation remain the biggest complaints. Most patients experience some level, which is why doses climb slowly.

Mono, dual, and triple agonists all share GLP-1, so Tschöp suspected that signal drives gut trouble. A bold question followed.

What if we come up with a version that’s GLP-1 free?

His team built a GIP-glucagon dual agonist. Tschöp says it cut body weight as much as retatrutide in mice, rats, and monkeys, without raising blood glucose.

No gastrointestinal side effects appeared in animals. Human trials are hoped for next year.

Animal data is only a first step, and Tschöp himself repeatedly notes that humans differ from mice. Clinical results will decide whether the promise holds.

Why Obesity Is a Brain Disease

Tschöp’s path began in 1994, when Jeffrey Friedman’s discovery of leptin in Nature revealed fat cells as an endocrine organ. Tschöp left clinical medicine to chase the field.

Ghrelin, the hunger hormone, followed in 2000. Both hormones act mostly in the brain, and genetics pointed the same direction.

In other words, science said obesity is a brain disease. So, if you want to target obesity, you probably have to target the brain.

Hitting the brain directly proved risky. Cannabinoid blockers cut appetite but brought cardiovascular and depression-related side effects.

His workaround: use Mother Nature’s toolkit, gut hormones that already report to the brain.

The Surprise: Nobody Fully Knows How These Drugs Work

There’s a lot we don’t know. So, one thing is we really don’t know how they work.

Decades of research targeted the hypothalamus, where leptin acts. These drugs work in the hindbrain, a different region entirely.

Much of what researchers believed about body-weight control is therefore disconnected from why these medications succeed. Tschöp calls it a lesson in serendipity.

Not the “Everything Drugs”

Headlines love sweeping claims. Tschöp pushes back.

They’re definitely not the everything drugs.

In his view, heart, cancer, and neurodegeneration benefits mostly flow from better metabolism and lower body weight. Direct effects likely involve addiction.

For my entire life I had these voices in my head that I need to eat and I need to think about food. And now I have like 5 hours more time in my day because these voices are gone.

Reports extend to alcohol, nicotine, and gambling. Tschöp stresses that long-term prospective studies are still missing, so evidence remains early.

Does joy fade? He says no depression signal has appeared, and people still enjoy meals. They just skip the second plate.

Muscle Loss: Real, But Not Drug-Specific

Tschöp says any weight loss strips fat and lean mass, whether through diet or medication. Muscle lacks receptors for these drugs.

His analogy: shedding 20 kg of fat is like dropping a heavy backpack, so the body needs less muscle. Older adults are different.

Tschöp, who is 59, agrees that regaining muscle gets harder with age. People who are not overweight face the steepest tradeoff.

Muscle-building add-ons are being developed, but he cautions against optimism. Myostatin inhibitors raise a snag.

Our heart is also a muscle. You want that to grow?

Microdosing and the Peptide Black Market

Would tiny doses benefit people who are not obese? Tschöp calls it plausible, noting that losing just 3 to 5% of body weight improves cardiovascular and metabolic health.

We don’t have the studies yet, right? This needs to be studied carefully and I’m not recommending it that, you know, don’t don’t do this at home.

Online sellers worry him more. Retatrutide is already circulating through catalogs, and anorexia nervosa patients could misuse such drugs.

Peptide hype also draws his skepticism. Some mushroom poisons are peptides too.

That doesn’t make peptides a good or a bad thing.

Affordability may ease demand. Synthesis costs, by his estimate, run under $10 per month, and competition plus expiring patents should lower prices.

Why Stopping Means the Weight Returns

Tschöp compares these drugs to blood pressure medication. Stop a beta blocker, and pressure climbs back.

You stopped taking the drug. The disease came back. That’s happening with most diseases.

Rebound arrives more slowly than predicted, possibly because active lifestyles form during treatment. Adaptive thermogenesis is also real, as the body burns fewer calories during restriction.

Responses differ, too. Some people carry weak GIP receptors, and Tschöp expects genetic screening to eventually match patients with fitting drug combinations.

How the Inventor Lives

• Exercise: five to six sessions weekly, mostly calisthenics and functional training, done first thing in the morning
• Sleep: seven to eight hours
• Diet: a constant battle against his sweet tooth
• Supplements: modest vitamins and fish oil

Some fun needs to be in there as well.

Tschöp also tried a dual agonist personally, starting during an Italian family vacation. Tiramisu lost its appeal, pasta portions shrank, and the gin tonic stopped tempting him.

You used to be more fun.

That was his brother-in-law’s verdict two weeks in. Tschöp is now considering a microdosing version.