Short‐term methionine deprivation improves metabolic health via sexually dimorphic, mTORCI‐independent mechanisms

Abstract

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.

Sex differences in the response to dietary restriction in rodents

“…This points to a hormonal regulation of bone morphology in response to MetR and highlights the importance of considering how sex steroids can alter experimental outcomes. Sexual dimorphism of hormonal responses was also observed in the response to short-term (up to 5 weeks) methionine deficiency in young mice [38]. While Met-deficient diets increase energy expenditure independent of sex, this was clearly linked to an increase in hepatic FGF21 expression and WAT Ucp1 only in males.…”

“…While Met-deficient diets increase energy expenditure independent of sex, this was clearly linked to an increase in hepatic FGF21 expression and WAT Ucp1 only in males. Furthermore, while activation of hepatic FGF21 expression was intact in males with constitutive mTORC1 activation, in females this alone was sufficient to activate FGF21 expression independent of diet [38]. While the molecular mechanism underlying these sex differences is not known, it is plausible to attribute these differences at least in part to sex hormones.…”

Restriction of essential amino acids dictates the systemic response to dietary protein dilution

“…By logical deduction, this meant that restriction of at least two, and perhaps all three, of these EAA were necessary for the full effects of DEAR. To initially test this, we then conducted a study where we singly restricted Lys, Thr, or Trp, at levels matching those found in the complete AA restriction, and could demonstrate that deprivation of either Thr or Trp, but not Lys, was sufficient to mimic the effects of DEAR ( To test the necessity of the deprivation of these two EAA for the effects of DEAR, we then conducted studies with selective add-back of these two EAA in the background of a low total AA supply, and could demonstrate that deprivation of both Thr and Trp were required for the systemic metabolic effects of DEAR ( Our prior studies were done on male mice from 8wks of age, which could potentially limit the applicability of our findings, as female mice are known to respond differently to dietary challenges [51][52][53] , and such young mice are still growing and thus may differ in dietary AA requirements compared with adult mice. Hence, we tested several diets used previously ( Fig.…”

“…3 wk). Thus, this may limit the applicability of the findings, especially since female mice can respond differently to dietary challenges [51][52][53] and AA requirements can be different during growth/maturation versus adulthood 50 . However, the majority of the effects of dietary AA restriction seen in young mice (i.e.…”

Lysosome: The metabolic signaling hub

“…Instead of directly sensing amino acid levels, SAMTOR binds to the metabolite S-adenosylmethionine (SAM), which disrupts its interaction with GATOR1, positioning SAMTOR as an indirect sensor of methionine. 84 Intriguingly, the discovery of SAMTOR provides the first molecular mechanism by which methionine restriction, a potent dietary intervention that improves metabolic health and extends rodent life span, [85][86][87] may mediate mTORC1 activity. [88][89][90] This study not only provides a key link between one carbon metabolism and the mTORC1 pathway but raises the question of whether additional intermediate metabolites in amino acid catabolism are also sensed by mTORC1.…”