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.
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.
|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|
|Kim, Jihyun; Fernand, Vivian E; Henagan, Tara M et al. (2016) Regulation of Brown and White Adipocyte Transcriptome by the Transcriptional Coactivator NT-PGC-1Î±. PLoS One 11:e0159990|
|Wanders, Desiree; Burk, David H; Cortez, Cory C et al. (2015) UCP1 is an essential mediator of the effects of methionine restriction on energy balance but not insulin sensitivity. FASEB J 29:2603-15|
|Lees, Emma Katherine; Krol, Elzbieta; Shearer, Kirsty et al. (2015) Effects of hepatic protein tyrosine phosphatase 1B and methionine restriction on hepatic and whole-body glucose and lipid metabolism in mice. Metabolism 64:305-14|
|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|
|Stone, Kirsten P; Wanders, Desiree; Calderon, Lucie F et al. (2015) Compromised responses to dietary methionine restriction in adipose tissue but not liver of ob/ob mice. Obesity (Silver Spring) 23:1836-44|
|Wanders, Desiree; Stone, Kirsten P; Dille, Kelly et al. (2015) Metabolic responses to dietary leucine restriction involve remodeling of adipose tissue and enhanced hepatic insulin signaling. Biofactors 41:391-402|
|Patil, Yuvraj N; Dille, Kelly N; Burk, David H et al. (2015) Cellular and molecular remodeling of inguinal adipose tissue mitochondria by dietary methionine restriction. J Nutr Biochem 26:1235-47|
|Lees, Emma K; KrÃ³l, ElÅ¼bieta; Grant, Louise et al. (2014) Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21. Aging Cell 13:817-27|
|Stone, Kirsten P; Wanders, Desiree; Orgeron, Manda et al. (2014) Mechanisms of increased in vivo insulin sensitivity by dietary methionine restriction in mice. Diabetes 63:3721-33|
Showing the most recent 10 out of 18 publications