The incidence of congenital portosystemic shunts (PSS) in widely used C57BL/6J mice is associated with cerebral glutamine accumulation^1,2 resulting from inefficient ammonia detoxification by the liver. In the presence of this vascular abnormality, portomesenteric blood bypasses the liver and drains directly to the systemic circulation. Under normal conditions, the liver receives nutrient- and hormone-rich portal blood, participating in the maintenance of fuel homeostasis. For example, the liver alone accounts for the uptake of about one third of an oral glucose load³ and extracts over one half of portal insulin⁴. Therefore, portosystemic shunting may have an important impact not only in blood detoxification, but also in liver-mediated metabolic control. In this study, we aimed at using high resolution gradient echo (GRE) MRI to visualize portosystemic shunts in mice. Moreover, we investigated eventual alterations in intra-hepatic metabolites by localized ¹H-MRS in vivo and in whole-body metabolism by evaluating glucose tolerance.11-week old male C57BL/6J mice, directly obtained from the Charles Rivers Laboratories (France) were scanned in the supine position under isofluorane anesthesia (1-2% in air:oxygen 50:50 mixture) with a ¹H quadrature surface coil (two 13 mm-inner-diameter physically decoupled loops) over the abdomen, in a 14.1 T-26 cm magnet interfaced to a Direct Drive console (VnmrJ, Agilent Technologies). Breathing rate and body temperature were monitored through an MR-compatible system, which also delivered respiratory gating signals for all MR acquisitions. Anatomical multi-slice GRE images of the liver were acquired in the coronal orientation (FOV = 25×25 mm², RO×PE = 256×192, TE = 5.2 ms, TR = ~600 ms when the respiration rate is 100 beats-per-minute, 30×0.3 mm slices without any gap, 8 averages). Among these mice, we detected 4 mice with abnormal liver images, in which we also confirmed the presence of high cerebral glutamine content, in the range of 5.6-8.6 mmol/g from the dorsal hippocampus, twice the value of source- and age-matched controls: 1.9-3.6 mmol/g (n=6, including two litter-mates). Based on the evidence of high cerebral glutamine associated with PSS¹, these mice are hence-after designated PSS-mice. For both PSS- and control-mice, water T₂ was calculated from localized ¹H-MR spectra obtained from a 8 µl voxel confined to the hepatic parenchyma with STEAM (TM = 20 ms; TR = 6.5 s; 32 scans), by mono-exponential fit of the signal decay with increasing TEs (5, 8, 10, 15, 20, 25, 30 ms). Hepatic lipid content (HLC) was also calculated from those spectra and expressed as the area of the bulk of methylene protons in hepatic fatty-acyl chains relative to that of the methylene protons plus water, with corrections for T₂. An oral glucose tolerance (OGTT) test was performed after a 6-h fasting. Glucose was monitored with a glucometer from tail tip samples before the glucose gavage (1.5 g/kg) and hence after until 2h. Fasting insulin was measured by ELISA immunoassay.Within approximately 15 minutes, GRE images were acquired with minimal motion artifacts and allowed the successful identification of PSS in mice (Figure 1). Maximum width and length of vascular shunts were calculated to be 2.9±0.1 mm and 1.1±0.2 mm, respectively. PSS-mice showed a different GRE image contrast when compared to controls (Figure 1) but hepatic water T₂ was 8.3±0.4 ms, similar to that found in control mice⁵. PSS-mice also showed increased HLC (Figure 2) and altered glucose homeostasis (Figure 3). Compared with controls, mice with PSS displayed lower fasting glycemia and insulinemia and hampered glucose clearance during the OGTT. These metabolic abnormalities are consistent with defects in hepatic glucose metabolism secondary to the lack of exposure to glucose itself and pancreatic hormones. Namely, portosystemic shunting would prevent glucagon-stimulated hepatic glucose production in the fasted state, and insulin-mediated hepatic actions that contribute to lower blood glucose upon the oral glucose load: stimulation of glycogen synthesis⁶ and inhibition of glucose output⁷. Our findings are in agreement with observations in humans reporting a deterioration of oral glucose tolerance in cirrhotic patients after portosystemic shunting⁸. Together with increased levels of hepatic lipids, impaired hepatic glucose metabolism, suggests a metabolic shift in fuel homeostasis, in favor of lipid utilization. In conclusion, we demonstrate that high resolution GRE MRI can be used to diagnose portosystemic shunts in mice; portosystemic shunting impacts intra-hepatic energy stores leading to hepatic lipid accumulation, and hampers the participation of the liver in the control of glucose homeostasis. In the long term, this hepatic metabolic shift may have deleterious consequences on both liver health and whole-body fuel homeostasis.