Infoscience

Conference paper

GLUT2-/- mice are resistant to age-induced accumulation of fat in the liver – an in vivo MRS study

Introduction: Whole-body energy balance is strongly dependent on the hepatic handling of metabolic fuels, which is affected by the hepatic lipid content (HLC). With in vivo nuclear magnetic resonance spectroscopy (MRS) HLC can be measured non-invasively and longitudinally. The study of mice is relevant for the characterization of transgenic models that provide insight into disease mechanisms but comparing with bigger subjects, the reduced sample size remains a limiting factor for in vivo MRS experiments. To overcome this sensitivity issue, we performed liver MRS in vivo at high field (14.1T) in wild-type C57BL/6J mice (WT) and GLUT2-/- mice that display altered whole-body energy balance. Methods: WT and GLUT2-/- mice reexpressing GLUT1 in the pancreatic β-cells to allow for survival and normal glucose-stimulated insulin secretion were studied at 4 months and 1 year of age. Non-fasted mice under isofluorane anesthesia were scanned in the supine position with a 1H quadrature surface coil over the abdomen. MRS measurements were performed in a horizontal bore 14.1T-26 cm magnet. Multi-slice gradient echo images were acquired for anatomical identification of the liver. Localized, respiration-gated 1H-MR spectra were acquired from a 10-15 µl voxel with STEAM with and without water suppression. HLC was estimated as the T2-corrected area of 1.3 ppm-lipid resonance relative to that of the water plus 1.3 ppm-lipid. Results/Discussion: Highly sensitive MRS at 14.1T allowed to accurately quantifying HLC in short experiments in mice. Suppression of the water signal revealed fatty-acyl resonances reflecting the lipid saturation profile. At 4 months, HLC was similar between WT and GLUT2-/-. HLC increased significantly in aged WT mice but remained low in aged GLUT2-/-. Also, the body weight of aged GLUT2-/- was slightly lower than that of WT. Low HLC in aged GLUT2-/- mice probably results from a defect on intra-hepatic pathway fluxes due to GLUT2 ablation in the liver. In addition, it may reflect altered utilization of metabolic substrates due to inadequate whole-body blood glucose sensing.

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