Obesity and diabetes are major 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-term
methionine deprivation (MD) regimen that preferentially reduces fat mass, restoring normal body weight and
glycemic control to diet-induced obese mice of both sexes. The benefits of MD do not accrue from calorie restriction, but instead result from increased energy expenditure. MD promotes increased energy expenditure in a sex-specific manner, inducing the
fibroblast growth factor (Fgf)-21-uncoupling
protein (Ucp)-1 axis only in males.
Methionine is an agonist 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 of MD. Our study sheds new light on the mechanisms by which dietary
methionine regulates metabolic health and demonstrates the translational potential of MD for the treatment of
obesity and
type 2 diabetes.-Yu, D., Yang, S. E., Miller, B. R., Wisinski, J. A., Sherman, D. S., Brinkman, J. A., Tomasiewicz, J. L., Cummings, N. E., Kimple, M. E., Cryns, V. L., Lamming, D. W. Short-term
methionine deprivation improves metabolic health via sexually dimorphic, mTORC1-independent mechanisms.