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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK105032-03
Application #
9388340
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Silva, Corinne M
Project Start
2015-12-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Lsu Pennington Biomedical Research Center
Department
Type
Organized Research Units
DUNS #
611012324
City
Baton Rouge
State
LA
Country
United States
Zip Code
70808
Morrison, Christopher D; Hao, Zheng; Mumphrey, Michael B et al. (2016) Roux-en-Y gastric bypass surgery is effective in fibroblast growth factor-21 deficient mice. Mol Metab 5:1006-14
Laeger, Thomas; Albarado, Diana C; Burke, Susan J et al. (2016) Metabolic Responses to Dietary Protein Restriction Require an Increase in FGF21 that Is Delayed by the Absence of GCN2. Cell Rep 16:707-16
Henagan, Tara M; Laeger, Thomas; Navard, Alexandra M et al. (2016) Hepatic autophagy contributes to the metabolic response to dietary protein restriction. Metabolism 65:805-15
Yu, Sangho; Qualls-Creekmore, Emily; Rezai-Zadeh, Kavon et al. (2016) Glutamatergic Preoptic Area Neurons That Express Leptin Receptors Drive Temperature-Dependent Body Weight Homeostasis. J Neurosci 36:5034-46