A gut sense for dietary lysine

About This Grant

SUMMARY As an essential amino acid, lysine is necessary for life. Accordingly, when exposed to a lysine-deficient diet, animals will seek out dietary lysine1. However, when animals are lysine-replete, lysine administration is a powerful inhibitor of overall food intake2. Despite this fine-tuned regulation of overall food consumption based on dietary lysine, the mechanism by which the body senses lysine is incompletely understood. A better understanding of lysine sensation has implications in obesity, as the “Protein Leverage Hypothesis” postulates that animals keep eating not for reward, but to meet their need for dietary protein3–5. As the rate-limiting amino acid in many diets, lysine has the potential to be a key factor in overall eating behavior. Our laboratory recently showed that specialized epithelial cells in the gut epithelium, neuropod cells, synapse on the vagal nerve to rapidly convey information about ingested sugar to the brain6,7. Prior research has shown that lesions of the vagal nerve prevent reductions in food intake caused by dietary lysine, but not other amino acids2. Therefore, it stands to reason that lysine sensation could depend on a gut-brain circuit beginning with neuropod cells. Our central hypothesis is that duodenal neuropod cells both detect lysine and drive lysine- seeking behavior when lysine is absent. This hypothesis is based on previous work as well as our observations that (1) knockout of taste receptors does not alter preference for amino acids following a protein deficient diet and (2) intraduodenal lysine activates the vagus nerve. The objectives of this project are two-fold: first, to determine the intestinal signal transduction pathway for lysine; and second, to evaluate neuropod cell- dependent lysine-seeking during exposure to a lysine-deplete diet. Our rationale is that by elucidating the mechanisms by which the gut senses lysine, signals the presence of lysine to the brain, and guides behavior towards lysine consumption during dietary lysine depletion, we can better understand the sensory biology underpinning chemosensation of a key amino acid in a way that could be leveraged in future therapeutics for obesity. Further, because we aim not only to determine how the body senses the presence of lysine, but how the absence of lysine alters gut-brain communication to guide ingestive behavior, this work has the potential to contribute to a better understanding of interoceptive mechanisms for essential nutrients as a whole.