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

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, we show that circulating levels of the metabolite para-tyramine-O-sulphate (pTOS) are increased more than 1,000-fold in pythons after a single meal. In pythons, pTOS production occurs in a microbiome-dependent manner via sequential decarboxylation and sulphation 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. Leveraging pythons as an extreme model of feeding and fasting behaviour, this study uncovers para-tyramine-O-sulphate as a conserved postprandial metabolite that links nutrient intake to energy balance by activating hypothalamic neurons and suppressing food intake in pythons and mice.