Mouse betaine-homocysteine S-methyltransferase deficiency reduces body fat via increasing energy expenditure and impairing lipid synthesis and enhancing glucose oxidation in white adipose tissue

Abstract

Betaine-homocysteine S-methyltransferase (BHMT) catalyzes the synthesis of methionine from homocysteine. In our initial report, we observed a reduced body weight in Bhmt-/-mice. We initiated this study to investigate the potential role of BHMT in energy metabolism. Compared with the controls (Bhmt+/+), Bhmt-/- mice had less fat mass, smaller adipocytes, and better glucose and insulin sensitivities. Compared with the controls, Bhmt-/- mice had increased energy expenditure, with no changes in food intake, fat uptake or absorption, or in locomotor activity. The reduced adiposity in Bhmt-/- mice was not due to hyperthermogenesis. Bhmt-/- mice failed to maintain a normal body temperature upon cold exposure because of limited fuel supplies. In vivo and ex vivo tests showed that Bhmt-/-mice had normal lipolytic function. The rate of 14C-labeled fatty acid incorporated into [14C] triacylglycerol was the same in Bhmt+/+ and Bhmt-/- gonadal fat depots (GWAT), but it was 62% lower in Bhmt-/- inguinal fat depots (IWAT) compared with that of Bhmt+/+ mice. The rate of 14C-labeled fatty acid oxidation was the same in both GWAT and IWAT from Bhmt+/+ and Bhmt-/- mice. At basal level, Bhmt -/- GWAT had the same [14C]glucose oxidation as did the controls. When stimulated with insulin, Bhmt-/- GWAT oxidized 2.4-fold more glucose than did the controls. Compared with the controls, the rate of [14C]glucose oxidation was 2.4- and 1.8-fold higher, respectively, in Bhmt-/- IWAT without or with insulin stimulus. Our results show for the first time a role for BHMT in energy homeostasis. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.