Compromised responses to dietary methionine restriction in adipose tissue but not liver of ob/ob mice

Objective Dietary methionine restriction (MR) reduces adiposity and hepatic lipids and increases overall insulin sensitivity in part by reducing lipogenic gene expression in liver, inducing browning of white adipose tissue (WAT), and enhancing the lipogenic and oxidative capacity of the remodeled WAT. Methods Ob/ob mice have compromised β-adrenergic receptor expression in adipose tissue and were used to test whether MR could ameliorate obesity, insulin resistance, and disordered lipid metabolism. Results In contrast to responses in wild-type mice, MR failed to slow accumulation of adiposity, increase lipogenic and thermogenic gene expression in adipose tissue, reduce serum insulin, or increase serum adiponectin in ob/ob mice. However, MR produced comparable reductions in hepatic lipids and lipogenic gene expression in both genotypes. In addition, MR was fully effective in increasing insulin sensitivity in adiponectin^-/- mice. Conclusions These findings show that diet-induced changes in hepatic lipid metabolism are independent of weight loss and remodeling of WAT and are not required for insulin sensitization. In contrast, the failure of ob/ob mice to mount a normal thermogenic response to MR suggests that the compromised responsiveness of adipose tissue to SNS input is an important component of the inability of the diet to correct their obesity and insulin resistance.