Metabolic effects of manganese

About This Grant

PROJECT SUMMARY The kinase Akt is a central mediator of insulin signaling. Its activation by insulin occurs when Akt is phosphorylated at two canonical sites, T308 and S473. Other covalent posttranslational modifications also contribute to Akt regulation, such as phosphorylation at alternative residues, acetylation, and ubiquitination. In this grant, we investigate a distinct mechanism of Akt activation: controlled access to a manganese (Mn2+) ion. Mn is an essential trace element that is acquired through the diet and excreted primarily via efflux from hepatocytes into bile. The efflux of Mn is mediated by the canalicular transporter Slc30a10. We have found in mice, cells, and in vitro that increased Mn availability directly promotes Akt activity in hepatocytes, in a manner that does not require upstream insulin signaling. The Mn-induced activation of Akt is sufficient to suppress glucose production, which provides a biochemical explanation for longstanding observations that Mn has glucose-lowering effects in humans and mice. Moreover, we have found that Mn availability is regulated nutritionally, via carbohydrate signaling. In this grant, we will use classic and state-of-the-art biochemical tools to investigate the cellular and biophysical features of the interaction between Akt and Mn. We will furthermore use genetic and dietary interventions in mice to investigate how control over Mn availability contributes to normal physiology and states of overnutrition. Success of this work will reveal a novel mechanism of regulating Akt activity and hepatic glucose production and generate new avenues for research in metabolism and cell signaling.