Python metabolomics uncovers a conserved postprandial metabolite and gut-brain feeding pathway

Xiao, S.; Wang, M.; Martin, T. G.; Scott, B.; Fang, X.; Liu, X.; Yang, Y.; Fu, S.; Truong, S. D.; Gugel, J. F.; Maas, G.; Mullen, M.; Hill, J. H.; Li, V. L.; Markhard, A. L.; Zhao, M.; Qi, W.; Reghupaty, S. C.; Spaas, J.; Wei, W.; Moholdt, T.; Hawley, J. A.; Voldstedlund, C. T.; Richter, E. A.; Chen, X.; Svensson, K. J.; Bernstein, D.; Leinwand, L. A.; Xu, Y.; Long, J. Z.

doi:10.64898/2026.01.09.698526

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bioRxiv · 10.64898/2026.01.09.698526

Python metabolomics uncovers a conserved postprandial metabolite and gut-brain feeding pathway

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Abstract

Most mammals consume small and frequent meals. By contrast, pythons are ambush predators that exhibit extreme feeding and fasting patterns and provide a unique model for uncovering molecular mediators of the postprandial response1-3. Using untargeted metabolomics, here we show that circulating levels of the metabolite para-tyramine-O-sulfate (pTOS) are increased >1,000-fold in pythons after a single meal. In pythons, pTOS production occurs in a microbiome-dependent manner via sequential decarboxylation and sulfation of dietary tyrosine. In both pythons and mice, pTOS administration activates a neural population in the ventromedial hypothalamus (VMH). In mice, these VMH neurons are required for the anorexigenic effects of pTOS. Chronic administration of pTOS to diet-induced obese male mice suppresses food intake and body weight. pTOS is also present in human blood, where its levels are increased after a meal. Together, these data uncover a conserved postprandial anorexigenic metabolite that links nutrient intake to energy balance.

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Xiao, S., Wang, M., Martin, T. G., Scott, B., Fang, X., Liu, X., Yang, Y., Fu, S., Truong, S. D., Gugel, J. F., Maas, G., Mullen, M., Hill, J. H., Li, V. L., Markhard, A. L., Zhao, M., Qi, W., Reghupaty, S. C., Spaas, J., Wei, W., Moholdt, T., Hawley, J. A., Voldstedlund, C. T., Richter, E. A., Chen, X., Svensson, K. J., Bernstein, D., Leinwand, L. A., Xu, Y., Long, J. Z.. 2026-01-11. Python metabolomics uncovers a conserved postprandial metabolite and gut-brain feeding pathway. https://doi.org/10.64898/2026.01.09.698526

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