Python Blood Could Change How We Lose Weight

Three days after swallowing a rat whole, a Burmese python’s blood is doing something extraordinary. Its heart has expanded by roughly a quarter. Its metabolism has accelerated thousands of times over. And coursing through its circulatory system is a molecule that, until now, nobody in the field of obesity research had thought to look for. Nobody thought to look inside a snake.

The molecule is called para-tyramine-O-sulfate, mercifully abbreviated to pTOS. In a fasted python, it is present at barely detectable levels. Then the snake eats. Within 72 hours, pTOS concentrations in its blood spike more than a thousandfold, a surge so dramatic that researchers at the University of Colorado Boulder spotted it immediately when they ran an untargeted metabolomics screen on postprandial python plasma. You don’t miss a thousand-fold change. It is, in the language of mass spectrometry, essentially a cliff.

The snakes in question were ball pythons and Burmese pythons housed in Leslie Leinwand’s laboratory at CU Boulder, where she has spent two decades studying what she calls the metabolic superpowers of large constrictors. Pythons can go a year or more without eating. When they do eat (prey equal in mass to themselves in a single meal), their internal organs undergo a controlled transformation that would be catastrophic in a mammal. The intestines double in size. The liver restructures itself. Protein synthesis ramps up across the body. And then, when digestion is complete, most of these changes reverse, cleanly, as if nothing happened. “You look at extraordinary animals that can do things that you and I and other mammals can’t do,” Leinwand said, “and you try to harness that for therapeutic interventions.”

The collaboration that produced the new work, published in Nature Metabolism, brought together Leinwand’s python biology expertise with the metabolomics laboratory of Jonathan Long at Stanford University. Long’s group had previously analysed racehorses, another animal with unusual metabolic demands, searching for blood molecules that enable elite athletic performance. “If we truly want to understand metabolism, we need to go beyond looking at mice and people and look at the greatest metabolic extremes nature has to offer,” Long said. A python that eats once a month and rewires its own physiology every time it does seemed, by that logic, worth a look.

What they found in pTOS surprised them. The molecule is a sulfated form of tyramine, which is itself derived from tyrosine, a common dietary amino acid. The pathway runs through the snake’s gut bacteria, which convert tyrosine to tyramine via bacterial enzymes; the tyramine then passes to the liver, where a specific sulfotransferase enzyme stamps a sulfate group onto it, producing pTOS. When the team treated pythons with antibiotics that wiped out their gut microbiome, the postprandial pTOS spike vanished almost entirely. The bacteria, it turns out, are essential.

But pTOS’s presence in pythons alone would make it an interesting curiosity, nothing more. The more consequential finding is what it does in mammals, and the fact that humans have some of it too. Checking existing metabolomics databases, the researchers found pTOS detected in 20 of 537 human blood studies, rising measurably after meals in most of the cohorts they examined. Mice and rats, oddly, seem to lack it almost completely, which may explain why pTOS has gone unnoticed for so long; the standard lab animals simply don’t have enough of it to find.

When the team administered pTOS to mice at doses calibrated to match python post-meal concentrations, the animals ate less. Considerably less, particularly in animals that had been made obese on a high-fat diet. Over 28 days of daily injections, the obese mice lost roughly 9 percent of their body weight relative to controls. Crucially, their water intake didn’t change. Their energy expenditure didn’t change. They moved normally. There was no sign of nausea (measured using a behavioural test in which mice can learn to associate a flavour with illness) and no elevation in blood pressure. The appetite suppression appeared, for want of a better word, clean. “We’ve basically discovered an appetite suppressant that works in mice without some of the side-effects that GLP-1 drugs have,” Leinwand said.

That comparison to GLP-1 drugs is deliberate and pointed. Ozempic, Wegovy and their relatives act by mimicking glucagon-like peptide-1, a gut hormone that slows digestion and signals fullness. They work well for many people, but studies suggest that as many as half of users stop within a year, often because of side effects including nausea, vomiting and, in some cases, substantial muscle loss. The GLP-1 drug class was itself inspired by a reptile: exendin-4, a peptide from the venom of the Gila monster, is the precursor molecule from which exenatide was developed. In a sense, pTOS represents a second chance for reptile pharmacology, drawing from a different source and operating through a different mechanism.

That mechanism runs through the ventromedial hypothalamus, a region deep in the brain long associated with feeding control and energy balance. Using a genetic technique that flags neurons activated by a specific stimulus, the researchers identified a population of VMH neurons that light up in response to pTOS. When they chemically silenced those neurons, pTOS lost most of its ability to suppress food intake in mice. The effect appears to be direct: pTOS crosses the blood-brain barrier, entering both the cerebrospinal fluid and brain tissue, and activates the VMH neurons independently of synaptic input from elsewhere. It finds the cells, in other words, and talks to them itself.

The same activation signal shows up in python brains, where pTOS administration triggers comparable cFos activity in the VMH region. This conservation across species, a molecule doing the same job in snakes and mammals via the same brain structure despite perhaps 300 million years of divergent evolution, is the finding the researchers find hardest to explain away. It suggests pTOS isn’t a peculiarity of python biology but rather a very old signalling system that most of the species we normally study happen to produce in quantities too small to notice. Leinwand and Long have formed a startup, Arkana Therapeutics, to pursue the commercial implications. Stanford has filed a provisional patent on pTOS for cardiometabolic diseases.

All of which leaves 207 other metabolites still to characterise. The pTOS screen was untargeted: the researchers weren’t looking for any particular molecule, just running the full postprandial chemistry of python blood through a mass spectrometer and seeing what changed. Some of those other compounds rose 500- to 800-fold. Nobody yet knows what they do. “We’re not stopping with just this one metabolite,” Leinwand said. “There’s a lot more to be learned.”

DOI / Source: https://doi.org/10.1038/s42255-026-01485-0

Frequently Asked Questions

What is pTOS and where does it come from?
Para-tyramine-O-sulfate (pTOS) is a small molecule found in the blood of pythons after they eat. It is produced through a two-step process: gut bacteria convert the dietary amino acid tyrosine into tyramine, which the liver then chemically modifies by adding a sulfate group. Without gut bacteria, the process doesn’t happen. Small amounts of pTOS are also present in human blood, and levels rise modestly after meals in most people studied.

How does pTOS suppress appetite without causing nausea?
Unlike GLP-1 drugs such as Ozempic, pTOS doesn’t appear to slow gastric emptying or alter levels of gut hormones associated with nausea. Instead, it crosses the blood-brain barrier and directly activates neurons in the ventromedial hypothalamus, a brain region that regulates feeding and energy balance. In mice, blocking those specific neurons removed most of pTOS’s appetite-suppressing effect, suggesting it works through a distinct and more targeted pathway.

Why haven’t we discovered pTOS before?
Most metabolism research uses mice and rats as model organisms, and those animals appear to have essentially no detectable pTOS in their blood. The molecule’s effects were therefore invisible in standard experimental systems. Pythons, which undergo one of the most dramatic metabolic transformations of any animal after eating, produce pTOS at concentrations a thousand times higher than their fasted baseline, making it far easier to detect and study.

Could pTOS become a weight-loss drug for humans?
It is far too early to say. The current research demonstrates effects in mice, and pTOS is detectable in human blood at low levels. The researchers have formed a startup, Arkana Therapeutics, and Stanford has filed a provisional patent on the compound, but the path from mouse studies to an approved human therapy typically takes many years and involves substantial clinical testing. The absence of the nausea side-effect seen with GLP-1 drugs, if it holds up in humans, would be clinically significant.

What other metabolites were found in python blood?
The researchers identified 208 metabolites that increased significantly in python blood after eating, with some rising 500- to 800-fold. pTOS was the most dramatic, at over a thousandfold. The functions of most of the other metabolites remain unknown and represent a large body of future research. The team has noted that age-related muscle loss, or sarcopenia, is one condition they hope python biology might eventually help address.