HNF4α-TET2-FBP1 axis contributes to gluconeogenesis and type 2 diabetes.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 40459008.
- Also identified by DOI 10.7554/eLife.103663 and PMC identifier 12133150.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The control of gluconeogenesis is critical for glucose homeostasis and the pathology of type 2 diabetes (T2D). Here, we uncover a novel function of TET2 in the regulation of gluconeogenesis. In mice, both fasting and a high-fat diet (HFD) stimulate the expression of TET2, and <i>TET2</i> knockout impairs glucose production. Mechanistically, FBP1, a rate-limiting enzyme in gluconeogenesis, is positively regulated by TET2 in liver cells. TET2 is recruited by HNF4α, contributing to the demethylation of the <i>FBP1</i> promoter and activating its expression in response to glucagon stimulation. Moreover, metformin treatment increases the phosphorylation of HNF4α on Ser313, which prevents its interaction with TET2, thereby decreasing the expression level of FBP1 and ameliorating the pathology of T2D. Collectively, we identify an HNF4α-TET2-FBP1 axis in the control of gluconeogenesis, which contributes to the therapeutic effect of metformin on T2D and provides a potential target for the clinical treatment of T2D.
Medical subject headings
- Gluconeogenesis
- Diabetes Mellitus, Type 2
- Hepatocyte Nuclear Factor 4
- DNA-Binding Proteins
- Proto-Oncogene Proteins