Short-Term methionine deprivation improves metabolic health via sexually dimorphic, mTORC1-independent mechanisms

Abstract

Obesity and diabetes aremajor challenges to global health, and there is an urgent need for interventions that promote weight loss. Dietary restriction of methionine promotes leanness and improves metabolic health in mice and humans. However, poor long-Term adherence to this diet limits its translational potential. In this study, we develop a short-Termmethioninedeprivation(MD)regimenthatpreferentially reduces fatmass, restoringnormalbodyweight and glycemic control to diet-induced obesemice of both sexes. The benefits ofMDdo not accrue fromcalorie restriction, but instead result from increased energy expenditure.MDpromotes increased energy expenditure in a sex-specific manner, inducing the fibroblast growthfactor (Fgf)-21-uncouplingprotein (Ucp)-1 axis only inmales.Methionine is anagonist of the protein kinase mechanistic target of rapamycin complex (mTORC)-1, which has been proposed to play a key role in the metabolic response to amino acid-restricted diets. In our study, we used a mouse model of constitutive hepatic mTORC1 activity and demonstrate that suppression of hepatic mTORC1 signaling is not required for the metabolic effects ofMD. Our study sheds new light on themechanisms by which dietarymethionine regulatesmetabolic health and demonstrates the translational potential ofMDfor the treatment of obesity and type 2 diabetes.