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

Area of Science:

• Metabolomics
• Neuroendocrinology
• Gut Microbiome Research

Background:

• Mammals typically eat small, frequent meals.
• Pythons, as ambush predators, have extreme feeding and fasting patterns, offering a unique model for postprandial studies.

Purpose of the Study:

• To identify molecular mediators of the postprandial response.
• To investigate the role of metabolites in regulating feeding behavior and energy balance.

Main Methods:

• Untargeted metabolomics to analyze circulating metabolites in pythons after feeding.
• Microbiome analysis to understand metabolite production pathways.
• Neural activation studies in pythons and mice.
• Administration of para-tyramine-O-sulphate (pTOS) in mice to assess its effects on food intake and body weight.

Main Results:

• Circulating para-tyramine-O-sulphate (pTOS) levels increased over 1,000-fold in pythons post-meal.
• pTOS production in pythons is microbiome-dependent, involving tyrosine decarboxylation and sulfation.
• pTOS administration activated a specific neural population in the ventromedial hypothalamus (VMH) in both pythons and mice.
• In mice, VMH neurons mediated the anorexigenic effects of pTOS.
• Chronic pTOS administration reduced food intake and body weight in diet-induced obese mice.
• pTOS is present in human blood and increases post-meal.

Conclusions:

• Para-tyramine-O-sulphate (pTOS) is a conserved postprandial anorexigenic metabolite.
• pTOS links nutrient intake to energy balance through VMH neural activation.
• This discovery opens new avenues for understanding and potentially treating metabolic disorders.