A molecule that increases by a thousandfold in ball pythons after they eat holds promise for a weight-loss drug.
Photo Credit: David Clode
Scientific Frontline: "At a Glance" Summary: Python-Derived Metabolite pTOS for Weight Loss
- Main Discovery: Researchers discovered that a metabolite known as pTOS, which drastically elevates in pythons after large meals, successfully reduces food intake and drives weight loss in obese laboratory mice.
- Methodology: Investigators compared blood profiles of fasted Burmese and Ball pythons before and after they ingested meals equal to 25 percent of their body weight. Upon identifying the most significantly elevated metabolite, pTOS, researchers administered the compound to obese mice to monitor subsequent changes in feeding behavior, metabolic rate, and body mass.
- Key Data: Post-feeding pTOS concentrations in python blood spiked by more than a thousandfold. When administered to obese mice, the treatment resulted in a 9 percent total body weight reduction over 28 days, driven entirely by decreased appetite rather than altered energy expenditure.
- Significance: The study isolates a novel gut-brain axis pathway where pTOS, produced via the bacterial breakdown of dietary tyrosine, travels to the hypothalamus to activate feeding-regulation neurons, functioning independently of traditional hormone pathways or gastric emptying rates.
- Future Application: The pTOS metabolite serves as a primary candidate for developing next-generation anti-obesity pharmaceuticals in humans, while the overarching strategy validates mining extreme animal metabolisms for therapeutic compounds targeting liver remodeling and beta-cell proliferation.
- Branch of Science: Endocrinology, Pathology, Metabolomics, Zoology.
- Additional Detail: Analyses of public human blood datasets revealed that pTOS normally increases only two to fivefold in humans after eating, demonstrating that the profound physiological extremes of the python were essential for isolating the molecule's functional signal.
Pythons don’t nibble. They chomp, squeeze and swallow their prey whole in a meal that can approach 100% of their body weight. But even as they slither stealthily around the forest, months or even a year may pass between massive mouthfuls. This pattern of extreme feasting and fasting taxes their metabolism far beyond what humans experience on a day-to-day basis.
Now researchers at Stanford Medicine and the University of Colorado, Boulder, have found that a metabolite that spikes a thousandfold in pythons after a large meal causes obese laboratory mice to shun their food pellets and lose weight — mimicking the effect of semaglutide drugs such as Ozempic and Wegovy.
Although it’s too soon to tell whether this metabolite, called pTOS, will translate to a new weight loss drug in humans, the study solidifies the power of studying extremes in the animal kingdom. Reptiles have repeatedly gifted humans with clinically significant drugs. Snake venom is chockful of biologically active compounds that have been developed into blood pressure medications and anticoagulants. And semaglutide arose from the discovery of a hormone in the Gila monster that regulates blood sugar levels.
Long is the senior author of the study, which was published March 19 in Nature Metabolism. Postdoctoral scholar Shuke Xiao, PhD; Mengjie Wang, MD, PhD, a postdoctoral scholar at the University of South Florida; and Thomas Martin, PhD, a postdoctoral scholar at the University of Colorado, Boulder, are the lead authors of the research.
Not exactly lab mice
Pythons aren’t common lab animals. They can weigh up to 200 pounds and live more than 20 years in the wild — a far cry from dainty laboratory mice. But their dramatic physiological response to sudden, large meals has drawn the attention of researchers. Within hours after eating, the pythons’ organs, including their hearts, begin to expand in size by 50% or more; their energy demands increase — digestion takes calories! — by more than 40%; and cells that don’t normally divide, like the insulin-producing beta cells in the pancreas, explode in number.
Researchers studying cardiac disease at the University of Colorado, Boulder, were interested in the sudden growth of the heart in pythons after feeding when they stumbled upon the metabolite. They examined blood from young Burmese pythons, weighing about 3.3 to 5.5 pounds, before and after a meal consisting of about 25% of their body weight. In the wild, Burmese pythons can go 12 to 18 months without eating; the laboratory snakes had fasted for 28 days prior to feeding. They conducted similar tests in Ball pythons — a smaller relative of the Burmese python.
The scientists identified more than 200 molecules called metabolites that increased in abundance at least 32-fold in the pythons’ blood within hours after eating, and 24 that decreased by an equal margin. One increased more than a thousandfold — a dramatic meal-induced spike. The molecule, which the researchers subsequently identified as pTOS, is a little-studied metabolite in humans and is mainly known as a molecule excreted in urine.
“We wondered whether this metabolite affected any of the post-feeding physiological changes in the snake,” Long said. “But when we administered pTOS to laboratory mice at levels similar to what we saw in the pythons after eating, we didn’t see any effect on energy expenditure, beta cell proliferation or organ size. What it did regulate was the appetite and feeding behaviors of the mice.”
The researchers found that obese mice given pTOS ate significantly less than control mice and, after 28 days, had lost 9% of their body weight when compared with control animals. The newly svelte mice showed no changes in water intake, energy expenditure or movement throughout the treatment. Additional experiments showed that the effect of pTOS is not due to changes in hormones known to regulate feeding or to a reduction in the rate of stomach emptying, which is one way common GLP-1 medications like Ozempic reduce appetite.
Further experiments determined that pTOS is a byproduct of the breakdown of tyrosine — an amino acid present in dietary protein — by bacteria in the gut. Treating the pythons with antibiotics prior to feeding abolished the eating-associated increase in pTOS levels.
“We were able to work out a pathway in which pTOS is produced after a meal through the metabolism of tyrosine in the gut and the liver,” Long said. “We also found that it then goes to a region of the brain called the hypothalamus, which is a well-known regulator of energy homeostasis. There it activates neurons involved in regulating feeding behaviors.”
The metabolite in humans
The researchers then studied six publicly available datasets of blood from healthy volunteers before and after a meal. In five of the six, pTOS levels were elevated after eating, but only by about two- to fivefold. Such a small increase in humans would be extremely difficult to pick out among many other feeding-associated metabolic changes — illustrating the value of using pythons as a model animal.
But a few people were more snakelike than others. One individual in the databases experienced a more than 25-fold increase in pTOS after a meal, reaching python-level concentrations in their blood. (Because these datasets were from previously conducted studies, it is not possible to know whether this person felt more full or ate less than other study participants.)
Although more research needs to be conducted into the possible use of pTOS in humans to curb appetite, the pythons gave the researchers a plethora of additional molecules to study.
“We’re generating a landscape of molecules that vary in prevalence after eating in all organs of these snakes,” Long said. “We already found many that look like hormones but that have no similarity with any known hormones in mice or humans. This is a form of natural product discovery.”
Long and his colleagues speculate that, like blood pressure medications and anticoagulants, some of these molecules could be clinically useful. “Maybe a patient with Type 1 diabetes due to defective beta cell function could benefit from a snake molecule that stimulates cell division, or a person with liver disease could take a snake-derived drug that facilitates organ remodeling,” Long said.
He noted that there’s an interest among scientists in augmenting human capabilities, such as creating vaccines that enhance the immune response. “Maybe this concept of using molecules first identified in snakes or other animals can extend to many other aspects of human health,” he said.
“We’re excited to learn from these snakes and other ‘extreme’ animals to inspire future discoveries,” he added.
Funding: The study was funded by the National Institutes of Health (grants R01GM029090, R01DK138518, R01DK105203, R01DK124265, K99DK141966, K99AR081618, F32HD112123, F32HL170637, F32DK138685 and T32GM142607), the Wu Tsai Human Performance Alliance, the Stanford Diabetes Research Center, the Phil and Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, the Ono Pharma Foundation, the Leducq Foundation, the American Heart Association, and the Stanford University Medical Scientist Training Program.
Published in journal: Nature Metabolism
Title: Python metabolomics uncovers a conserved postprandial metabolite and gut–brain feeding pathway
Authors: Shuke Xiao, Mengjie Wang, Thomas G. Martin, Barry Scott, Xing Fang, Xinming Liu, Yongjie Yang, Sipei Fu, Steven D. Truong, Jack F. Gugel, Gregory L. Maas, Marcus P. Mullen, Jennifer Hampton Hill, Veronica L. Li, Andrew L. Markhard, Mingming Zhao, Wei Qi, Saranya C. Reghupaty, Meng Zhao, Jan Spaas, Wei Wei, Trine Moholdt, John A. Hawley, Christian T. Voldstedlund, Erik A. Richter, Xiaoke Chen, Katrin J. Svensson, Daniel Bernstein, Leslie A. Leinwand, Yong Xu, and Jonathan Z. Long
Source/Credit: Stanford School of Medicine | Krista Conger
Reference Number: bio031926_02
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