The diabetes gene Tcf7l2 organizes gene expression in the liver and regulates amino acid metabolism

Objective

Though Tcf7l2 harbors the strongest genetic association with diabetes identified thus far, how it promotes metabolic disease remains unclear. Our aim was to dissect the contribution of hepatic TCF7L2.

Methods

Mice with liver-specific knockout of Tcf7l2 produced by targeted deletion of exon 1 were subjected to physiological characterization, single nucleus sequencing, and metabolite profiling. In parallel, a phenome-wide association study was performed in humans.

Results

We found that liver-specific deletion of Tcf7l2 had little effect on plasma glucose, but disrupted hepatic zonation. That is, many genes normally show gradients of expression across the liver lobule; in the absence of Tcf7l2, these gradients collapsed. One major consequence was 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, glutamine was found to be the most significantly decreased metabolite in the plasma of individuals harboring the rs7903146 variant in Tcf7l2.

Conclusions

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.