Work

Targeting negative phosphorylation to activate AMPK

Year: 2025

Type: article

Abstract: AMPK is a master regulator of metabolism and is highly conserved and ubiquitously expressed. Activation of AMPK stimulates the catabolic pathway (glucose utilization and β-oxidation) and inhibits the anabolic pathway (gluconeogenesis, protein synthesis, and lipogenesis), leading to improvement of cellular energy status. However, the mechanisms of maintaining low cellular AMPK activity are not fully understood. We and other investigators showed that activated PKA in the glucagon-cAMP signaling pathway and insulin-activated AKT both can directly phosphorylate AMPKα1/2 at S496/491 to inhibit AMPK activity. In the current study, we found that activation of AMPK by an activator, AICAR, led to elevated and prolonged phosphorylation of AMPKα1/2 at S496/S491, reflecting a feedback inhibition of AMPK activity. In an in vitro assay, functional AMPKα1β1γ1 or AMPKα2β1γ1 can phosphorylate AMPKα1 at S496 or AMPKα2 at S491, respectively. We designed and successfully screened a new AMPKα2-targeting peptide to activate AMPK through competitively blocking the negative phosphorylation, resulting in suppression of gluconeogenic gene expression and promotion of mitochondrial fission in hepatocytes.

Source: Endocrine Connections

DOI: 10.1530/ec-25-0260

Authors: Alexia Pearah, Balamurugan Ramatchandirin, Karina Ramirez, Sally Radovick, Fredric E Wondisford, Ling He

Institutions: Johns Hopkins University, Johns Hopkins Medicine, University of Arizona

Language: English

Topic: Metabolism, Diabetes, and Cancer

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,146