Neural mechanisms underlying the prioritization of protein-rich foods during protein need states

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Pennington Biomedical Research Center $251,580 on April 3, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to investigate the neural mechanisms underlying protein-food preference during protein-need states.

The research examines how the brain discerns and values dietary protein by assessing animals' ability to learn and associate intestinal protein cues with novel flavors, evaluating the roles of vagal transmission and FGF21 signaling in the brain. The work also determines whether intestinal protein cues activate dopamine neurons and whether beta-klotho (KLB) neurons project to these dopamine neurons, thereby influencing the reward value of protein. The project builds on prior findings that protein restriction drives adaptive changes in feeding behavior through FGF21 signaling, shifting macronutrient preference from carbohydrates to protein and heightening motivation toward protein. This research seeks to clarify the mechanisms by which protein-restricted animals distinguish and prioritize foods based on protein content and to bridge the gap in understanding macronutrient preferences, with potential application to developing tailored nutritional interventions for healthy eating.

Performance occurs in Baton Rouge, Louisiana, with completion targeted for September 2, 2027. Pennington Biomedical Research Center is a Louisiana State University–affiliated research institution that operates research cores in mass spectrometry, MRI, clinical metabolic assessment, and biorepository to support funded research.

Abstract

Dietary protein or essential amino acid intake is crucial for survival, and evidence indicates that the body adaptively responds to reductions in protein intake by altering its feeding behavior. The morrison lab has previously shown that these adaptive changes in feeding behavior under protein restriction are driven by FGF21 signaling in the brain through its interaction with the CO- receptor beta-klotho (KLB). Specifically, protein restriction leads to an increase in food intake, a shift in macronutrient preference from carbohydrates to protein, and heightened motivation toward protein, all of which are reliant on FGF21 signaling in the brain. However, the mechanism by which protein-restricted animals distinguish and prioritize foods based on their protein content remains unclear. Therefore, the goal of this F32 project is to understand how the brain discerns and values dietary protein by: 1) assessing animals' ability to learn and associate intestinal protein cues with novel flavors, evaluating the roles of vagal transmission and FGF21 signaling, and 2) determining whether intestinal protein cues activate dopamine neurons in the brain and if KLB neurons project to these dopamine neurons, thereby influencing the reward value of intestinal protein. This research will shed light on the interaction between short-term meal-related protein signals and the long-term protein restriction signal, FGF21. Ultimately, IT seeks to bridge the GAP in our understanding of macronutrient preferences, which has predominantly focused on fats and carbohydrates, thereby deepening our insight into the complex decision-making processes behind food choices. This could lead to the development of tailored nutritional interventions aimed at promoting healthy eating habits in individuals struggling to maintain a healthy diet.