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Glucose is a ubiquitous and essential source of energy for all living organisms. Although mammals have evolved ways to convert other nutritional molecules to ATP, the preference for dietary glucose appears to be preserved. In rodents, the immediate detection of ingested glucose potently reinforces intake, hierarchically organizing behaviors towards glucose-yielding substances, and away from other types of food including other sugars. Taste is the primary sense linked to nutrient selection. Until recently, it was thought that most mammalian species utilize a single broadly tuned receptor to detect all simple sugars. Indeed, this “sweet” receptor, which comprises a heterodimer of the T1R2 and T1R3 proteins, binds multiple natural sugars (e.g., glucose, fructose, sucrose, maltose), as well as various other chemicals that yield little to no energy (e.g., low calorie sweeteners, sugar alcohols) and some d-amino acids. The neural signal originating from the sweet receptor is hardwired into brain circuits that drive eating and drinking behaviors, but it is an unreliable indicator of nutrient quality and quantity.

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The diet-derived gut microbial metabolite 3-phenylpropionic acid reverses insulin resistance and obesity-associated metabolic dysfunction

Sara Alqudah, Beckey DeLucia, Lucas J. Osborn, Rachel L. Markley, ... Jan Claesen

The diet-derived gut microbial metabolite 3-phenylpropionic acid reverses insulin resistance and obesity-associated metabolic dysfunction

 

Background/Purpose

Obesity-associated metabolic disorders, including type 2 diabetes and metabolic dysfunction associated fatty liver disease (MAFLD), are major global health burdens. While dietary polyphenols have shown promise in ameliorating these conditions, their efficacy is dependent on specialized gut microbial metabolism, and the underlying molecular mechanisms remain mostly elusive. Here, we demonstrate that dietary supplementation with polyphenol-rich elderberry (Eld) extract abrogates the effects of an obesogenic diet in a gut microbiota-dependent manner, preventing insulin resistance and reducing hepatic steatosis in mice.

Methods

We developed a targeted, quantitative liquid chromatography-tandem mass spectrometry method for detection of gut bacterial polyphenol catabolites and identified 3-phenylpropionic acid as a key microbial metabolite in the portal plasma of Eld supplemented animals.

Results

We showed that 3-phenylpropionic acid potently activates hepatic AMP-activated protein kinase α, explaining its role in improved liver lipid homeostasis. We further uncovered the metabolic pathway cumulating in 3-phenylpropionic acid for the common gut commensal Clostridium sporogenes.

Conclusion

Our findings establish 3-phenylpropionic acid as a diet-derived, microbiota-dependent metabolite with insulin-sensitizing and anti-steatotic activities and provide a molecular basis for prebiotic interventions to improve host metabolic health.