Dietary methionine restriction (MR) produces a highly integrated series of biochemical and physiological responses that reduce adiposity, improve biomarkers of metabolic health and enhance insulin sensitivity. Our data make a compelling case that dietary MR acts through both centrally-mediated effects on energy balance, and direct effects on peripheral tissues that remodel white adipose tissue, activate thermogenesis in brown adipose tissue, and enhance insulin sensitivity. We hypothesize that sensing of dietary MR is coupled to these responses through hepatic sensing of reduced methionine through a glutathione-dependent mechanism that activates CREBH and the eIF2 kinase, PERK. The activation of CREBH and PERK results in activation eIF2?- and NRF2-dependent transcriptional programs that increase hepatic expression and release of FGF21. We hypothesize that the increase in FGF21 acts through direct and centrally-mediated mechanisms to activate thermogenesis, increase energy expenditure, reduce fat deposition, and enhance overall insulin sensitivity. We will use a combination of in vivo metabolic phenotyping and ex vivo biochemical analysis with loss of function animal models to examine the role of essential amino acid sensing in the respective responses to dietary MR. The goal of this work is to identify the nutrient sensing and signaling systems which detect the restriction of methionine and translate this dietary modification into a highly integrated and beneficial set of physiological responses.

Public Health Relevance

Obesity and metabolic disease represent a growing health problem in the world and predispose affected individuals to developing more serious diseases including diabetes, heart disease, and stroke. Dietary methionine restriction produces a highly integrated series of biochemical and physiological responses that reduce adiposity, improve biomarkers of metabolic health and enhance insulin sensitivity. The pre-clinical studies proposed herein represent proof of concept testing and discovery to facilitate the development of diet-based approaches that will translate into effective treatments for metabolic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK096311-08
Application #
9896807
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Teff, Karen L
Project Start
2012-07-01
Project End
2021-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
8
Fiscal Year
2020
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
Forney, Laura A; Stone, Kirsten P; Wanders, Desiree et al. (2018) The role of suppression of hepatic SCD1 expression in the metabolic effects of dietary methionine restriction. Appl Physiol Nutr Metab 43:123-130
Wanders, Desiree; Forney, Laura A; Stone, Kirsten P et al. (2018) The Components of Age-Dependent Effects of Dietary Methionine Restriction on Energy Balance in Rats. Obesity (Silver Spring) 26:740-746
Forney, Laura A; Stone, Kirsten P; Wanders, Desiree et al. (2018) Sensing and signaling mechanisms linking dietary methionine restriction to the behavioral and physiological components of the response. Front Neuroendocrinol 51:36-45
Hao, Zheng; Leigh Townsend, R; Mumphrey, Michael B et al. (2018) Roux-en-Y Gastric Bypass Surgery-Induced Weight Loss and Metabolic Improvements Are Similar in TGR5-Deficient and Wildtype Mice. Obes Surg :
Ghosh, Sujoy; Forney, Laura A; Wanders, Desiree et al. (2017) An integrative analysis of tissue-specific transcriptomic and metabolomic responses to short-term dietary methionine restriction in mice. PLoS One 12:e0177513
Forney, Laura A; Wanders, Desiree; Stone, Kirsten P et al. (2017) Concentration-dependent linkage of dietary methionine restriction to the components of its metabolic phenotype. Obesity (Silver Spring) 25:730-738
Wanders, Desiree; Forney, Laura A; Stone, Kirsten P et al. (2017) FGF21 Mediates the Thermogenic and Insulin-Sensitizing Effects of Dietary Methionine Restriction but Not Its Effects on Hepatic Lipid Metabolism. Diabetes 66:858-867
Pettit, Ashley P; Jonsson, William O; Bargoud, Albert R et al. (2017) Dietary Methionine Restriction Regulates Liver Protein Synthesis and Gene Expression Independently of Eukaryotic Initiation Factor 2 Phosphorylation in Mice. J Nutr 147:1031-1040
Wanders, Desiree; Stone, Kirsten P; Forney, Laura A et al. (2016) Role of GCN2-Independent Signaling Through a Noncanonical PERK/NRF2 Pathway in the Physiological Responses to Dietary Methionine Restriction. Diabetes 65:1499-510
Grant, Louise; Lees, Emma K; Forney, Laura A et al. (2016) Methionine restriction improves renal insulin signalling in aged kidneys. Mech Ageing Dev 157:35-43

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