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.; Zhao, M.; 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.
Show 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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