Siyuan Liu

Introduction: A consequence of modernization is that people have adopted diets for which they are poorly adapted. This has contributed to a rise in the prevalence of metabolic diseases including obesity and non-alcoholic fatty liver disease. Prior research has shown that restricting dietary methionine results in increased energy expenditure that is accompanied by lower adiposity and liver fat accumulation. The mechanisms by which restricting dietary methionine elicits these beneficial metabolic outcomes remain unclear. Liver gluconeogenesis is an energy (ATP) consuming process. Our studies tested the role of liver gluconeogenesis in the metabolic actions of dietary methionine restriction. Methods: Experiments used mice with a liver-specific knockout of cytosolic phosphoenolpyruvate carboxykinase to inhibit liver gluconeogenesis and wild-type (WT) littermates. Mice received a control diet (0.86% w/w methionine) or a methionine-restricted diet (0.172% w/w). Following six weeks on diet, body composition was measured with by NMR. 2H/13C metabolic flux analysis was performed in conscious, unrestrained mice to quantify liver gluconeogenesis and associated nutrient fluxes. Liver triacylglycerides and adenine nucleotides were determined to assess liver lipid content and energy state, respectively. Results: WT mice fed a methionine-restricted diet showed higher liver gluconeogenesis compared to WT mice on a control diet (1.36 vs. 1.14 µmol/kg/min). This was associated with a ~25% decline in liver ATP and ~3-fold reduction in liver triacylglycerides in WT mice receiving a methionine-restricted diet. Dietary methionine restriction lowered body weight and fat mass in WT mice. Notably, this reduction in adiposity was abolished in mice lacking liver phosphoenolpyruvate carboxykinase. Conclusion: An increase in gluconeogenesis is required for dietary methionine restriction to lower adiposity. This may be due to an energy deficit created by the elevated gluconeogenesis.