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 lipid metabolism and enhance insulin sensitivity. We hypothesize that sensing of dietary MR is coupled to these responses through a combination of essential amino acid- dependent signaling and methionine-specific effects on cell glutathione which serve to enhance insulin signaling. 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. These studies will be complemented by a two-pronged in vivo and in vitro approach to establish the specificity of restricting dietary methionine versus other essential amino acids. 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. The significant unanswered question addressed by this proposal is whether and how restriction of methionine provides significant additional benefits compared to restriction other essential amino acids.

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 #
5R01DK096311-03
Application #
8686834
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Silva, Corinne M
Project Start
2012-07-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Lsu Pennington Biomedical Research Center
Department
Type
Organized Research Units
DUNS #
City
Baton Rouge
State
LA
Country
United States
Zip Code
70808
Forney, Laura A; Stone, Kirsten P; Wanders, Desiree et al. (2017) Sensing and signaling mechanisms linking dietary methionine restriction to the behavioral and physiological components of the response. Front Neuroendocrinol :
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
Forney, Laura A; Stone, Kirsten P; Wanders, Desiree et al. (2017) The role of suppression of hepatic SCD1 expression in the metabolic effects of dietary methionine restriction. Appl Physiol Nutr Metab :1-8
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
Kim, Jihyun; Fernand, Vivian E; Henagan, Tara M et al. (2016) Regulation of Brown and White Adipocyte Transcriptome by the Transcriptional Coactivator NT-PGC-1?. PLoS One 11:e0159990
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, T M; Cefalu, W T; Ribnicky, D M et al. (2015) In vivo effects of dietary quercetin and quercetin-rich red onion extract on skeletal muscle mitochondria, metabolism, and insulin sensitivity. Genes Nutr 10:451

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