Enhanced metabolic benefits of dietary methionine restriction in cold resistant hybrid UCP1-deficient mice

Dietary methionine restriction (MR) improves metabolic health in various animals. Beneficial effects on mice include reduced obesity and improved metabolism associated with the appearance of multilocular uncoupling protein 1 (UCP1) positive adipocytes in white fat. This suggests that MR-induced UCP1 thermogenesis contributes significantly to metabolic health. To test this, we evaluated MR effects using unique UCP1-deficient mice on a hybrid (F1) background that is resistant to developing hypothermia upon acute cold exposure. F1.Ucp1^HET and F1.Ucp1^KO mice were fed high fat control diet (HF-CD) and then switched to a high fat MR diet (HF-MRD). Indirect calorimetry was used to monitor energy metabolism; and, serum hormones, metabolites, tissue gene expression, and histology were evaluated. While both genotypes showed improved metabolic parameters when fed HF-MRD, F1.Ucp1^KO mice exhibited further changes in iWAT morphology and more pronounced metabolic improvements in glucose tolerance, serum metabolic biomarker profiles and hepatic steatosis compared to F1.Ucp1^HET. Strikingly, F1.Ucp1^KO mice showed elevated fatty acid oxidation compared with F1.Ucp1^HET when fed high fat control diet (HF-CD) that was sustained after the switch to HF-MRD. We posit that F1.Ucp1^KO mice employ fatty acid oxidation for body temperature maintenance as at least a part of a mechanism that protects them from acute exposure to cold temperatures in addition to development of diet-induced obesity. Furthermore, our studies suggest that many of the metabolic benefits of MR in mice do not require functional UCP1 thermogenesis.