The restriction of dietary protein intake induces adaptive changes in metabolism and increases lifespan, but the cellular mechanisms mediating the detection of dietary protein restriction and its effects on health and longevity are virtually undescribed. We recently discovered that the hormone FGF21 is robustly induced by dietary protein restriction, and that mice lacking FGF21 fail to alter food intake, energy expenditure or body weight in response to dietary protein restriction. These data not only redefine the physiological role for FGF21, they also identify a fundamentally novel endocrine mechanism that appears to explain the metabolic effects of protein restriction. This project extends these data by 1) Identifying the cellular mechanism whereby dietary protein restriction increases hepatic FGF21, 2) Determining whether FGF21 signaling within the CNS or adipose tissue is required for the effects of dietary protein restriction on energy expenditure, and 3) Delineating the mechanisms through which protein restriction protects against HFD-induced obesity and glucose intolerance. This project will redefine the physiological role of FGF21 in the adaptive responses to nutrient restriction and provide a novel mechanistic explanation for the relationship between dietary protein, metabolism and health.
This project focuses on the molecular mechanisms connecting dietary macronutrient composition and metabolism. Our data identify FGF21 as a critical endocrine signal for dietary protein restriction. This project will further test this funcional relationship by definitively determining whether FGF21 is an essential mediator of the metabolic and behavioral responses to dietary protein restriction. This project will exert a significant and sustained impact on the field by identifying molecular detectors of protein availability, redefinin the physiological role of FGF21, and identifying new dietary and molecular strategies for the regulation of metabolism.
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