The Diabetes Gene Tcf7l2 Organizes Gene Expression in the Liver and Regulates Amino Acid Metabolism

TCF7L2 harbors the strongest genetic association with diabetes identified thus far. However, its function in liver has remained unclear. Here, we find using mice with liver-specific deletion, that Tcf7l2 plays a central role in maintaining hepatic zonation. That is, in the normal liver, many genes show gradients of expression across the liver lobule; in the absence of Tcf7l2, these gradients collapse. One major consequence is the disorganization of glutamine metabolism, with a loss of the glutamine production program, ectopic expression of the glutamine consumption program, and a decrease in glutamine levels. In parallel, metabolomic profiling shows glutamine to be the most significantly decreased metabolite in individuals harboring the rs7903146 variant in TCF7L2. Taken together, these data indicate that hepatic TCF7L2 has a secondary role in glycemic control, but a primary role in maintaining transcriptional architecture and glutamine homeostasis. Overall design: Tcf7l2Flox/Flox mice20 were purchased from Jackson Laboratories (strain code: 031436) and group-housed at 21 °C on a 12 hour light/dark cycle (7 am/7 pm) with free access to food, unless otherwise indicated. At the end of the experiment, mice were killed in the ad libitum state at 2 pm EST to collect plasma and tissues. All animal experiments were performed under approval of the Institutional Animal Care and Research Advisory Committee (IACUC) at Boston Children's Hospital. Tcf7l2Flox/Flox littermates were injected retro-orbitally at five to seven weeks of age with 1 x 1011 genome copies of AAV8-TBG-GFP (CON, Penn Vector Core, 105535-AAV8) or AAV8-TBG-CRE (TCF7L2 L-KO, Penn Vector Core 107787-AAV8). They were then placed on a Western Diet (Envigo, TD.88137, irradiated, 42% kcal from fat, 0.2% cholesterol, and 34% sucrose by weight) for twelve weeks.