Dietary Methionine Restriction Signals to the Brain Through Fibroblast Growth Factor 21 to Regulate Energy Balance and Remodeling of Adipose Tissue.

OBJECTIVE Restricting dietary methionine to 0.17% in mice increases energy expenditure (EE), reduces fat deposition, and improves metabolic health by increasing hepatic fibroblast growth factor 21 (FGF21). The goal of this study was to compare each of these responses in mice with the coreceptor for FGF21 deleted in either adipose tissue or the brain. METHODS Methionine-restriction (MR) diets were fed to age-matched cohorts of mice with the coreceptor for FGF21 deleted in either adipose tissue or the brain. The physiological and transcriptional responses to MR were compared in the respective cohorts. RESULTS Tissue-specific deletion of the FGF21 coreceptor in adipose tissue did not abrogate the ability of dietary MR to increase  EE and reduce fat deposition. Tissue-specific deletion of the FGF21 coreceptor from the brain produced mice that were unable to respond to the effects of MR on  EE or the remodeling of adipose tissue. CONCLUSIONS The increase in FGF21 produced by dietary MR acts primarily in the brain to produce its physiological effects on energy balance. In contrast, the effects of MR on hepatic gene expression were intact in both models, supporting a mechanism that directly links detection of reduced methionine in the liver to transcriptional mechanisms that alter gene expression in the liver.