Role of General Control Nonderepressible 2 (GCN2) kinase in mediating responses to dietary methionine restriction

Abstract

Restriction of dietary methionine from normal levels (0.86%) to 0.17% produces a coordinated series of biochemical and physiological responses that improve biomarkers of metabolic health, limit fat accretion, and enhance insulin sensitivity. GCN2 kinase serves as a sensor to detect reductions in essential amino acids and initiates integrated behavioral and transcriptional responses that mediate metabolic adaptation. The role of GCN2 in mediating the responses to dietary methionine restriction (MR) was assessed using GCN2−/− mice. Dietary MR for 8 wks produced a comparable reduction in hepatic triglyceride and increase in food consumption in wild type (WT) and GCN2−/− mice, while the normal diet‐induced increase in plasma adiponectin was actually enhanced in GCN2 nulls. The transcriptional responses produced by dietary MR in brown adipose tissue did not differ between WT and GCN2 null mice. In contrast, the diet‐induced increase in energy expenditure and reductions in fasting insulin and hepatic SCD‐1 expression observed in WT mice were partially compromised in GCN2 nulls, and the normal reductions in adiposity, plasma leptin and glucose were absent in GCN2−/− mice. The present findings suggest that GCN2 is an important component of the nutrient sensing mechanism(s) linking restriction of dietary methionine to the metabolic adaptations produced by the diet. Work supported by NIH: 2 P20 RR021945 (TWG), 2 U24 DK076169 (TWG), 1 F32 DK088513 (EPP), 1 RO1 HD070487 (TGA).Grant Funding Source: NIH