The effects of sex and age on the metabolic response to methionine deprivation, a novel intervention for the treatment of obesity and diabetes

Obesity has become an increasing health problem in the United States and worldwide; effective interventions that promote weight loss are urgently needed. 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. To address this problem, we have developed short‐term methionine deprivation as a rapid and effective strategy to reduce adiposity and promote metabolic health. We examined the effects of a short‐term MD regimen on the metabolic health of C57BL/6J mice of both sexes, including 1) young mice raised on a chow diet; 2) young mice preconditioned with a Western high‐fat, high‐sucrose diet for 12 weeks; and 3) aged mice on a chow diet. We examined weight, body composition, glucose and insulin tolerance, food intake, activity and energy expenditure. We further examined hepatic steatosis and gene expression in multiple tissues. Using metabolomic and proteomic approaches, we also determined methionine metabolite levels and evaluated global histone post‐translational modification profiles in the liver. Finally, as dietary methionine is an agonist of the protein kinase mTORC1 (mechanistic Target of Rapamycin Complex 1), which is proposed to play a key role in the metabolic response to amino acid‐restricted diets, we examined the role of hepatic mTORC1 in the metabolic response to MD using a mouse model of constitutive hepatic mTORC1 activity. We find that a short‐term MD regimen preferentially reduces fat mass, restoring normal body weight and glycemic control to diet‐induced obese mice of both sexes. Additionally, we have examined the persistence of these metabolic changes in young and aged mice. We find that the benefits of MD do not accrue from calorie restriction, but instead result from increased energy expenditure. Intriguingly, MD promotes increased energy expenditure in both sexes, but induces the FGF21‐UCP1 axis only in males. We also observed sex‐specific effects of MD on lipid metabolism. The metabolic analysis revealed that MD significantly decreases levels of methionine as well as the methionine metabolite SAM ( S ‐adenosyl methionine) in the liver, and that accordingly, histone methylation in the liver is dramatically downregulated compared to control. Furthermore, using liver‐specific TSC1 knockout mice, which have constitutively active hepatic mTORC1, we determined that the metabolic effects of MD do not depend upon reduced hepatic mTORC1 signaling. Our study sheds new light on the mechanisms by which dietary methionine regulates metabolic health. In particular, our results suggest that sex‐dependent mechanisms may mediate the metabolic response to decreased dietary methionine, and that the FGF21‐UCP1 axis may be dispensable for the metabolic benefits of MD in females. Our results also demonstrate that the metabolic benefits of MD are not mediated by suppression of hepatic mTORC1 signaling. Our study clearly demonstrates the translational potential of MD or MD‐mimetics for the treatment of obesity and type 2 diabetes, diseases which are highly prevalent in the aged. Support or Funding Information This research was supported in part by grants from the NIH AG041765 (D.W.L.), AG050135 (D.W.L.), AG051974 (D.W.L.), GM059789‐15/P250VA (J.M.D), a New Investigator Program Award (D.W.L.) and a Collaborative Health Sciences Program Award (V.L.C.) from the Wisconsin Partnership Program, the V. Foundation for Cancer Research (V.L.C.), and a Glenn Foundation Award for Research in the Biological Mechanisms of Aging (D.W.L.), as well as startup funds from the UW‐Madison School of Medicine and Public Health and the UW‐Madison Department of Medicine (V.L.C. and D.W.L.). This research was conducted while D.W.L. was an AFAR Research Grant recipient from the American Federation for Aging Research. D.Y. is supported in part by a fellowship from the American Heart Association (17PRE33410983). S.A.H. is supported by a training grant from the NIH/NIDDK (T32DK007665). This work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital. This work does not represent the views of the Department of Veterans Affairs or the United States Government. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .