2025 Theses Doctoral

Manganese Modulates Hepatic Insulin Signaling and Metabolism

Gamarra, Jennifer Rose

Manganese (Mn) is an essential trace element exclusively acquired through the diet. While known to be essential for life, research on Mn has significantly lagged behind studies of other elements because of the lack of robust tools to measure Mn concentrations and for many years it was difficult to manipulate both cell and tissue levels of Mn because the transporters that regulate Mn homeostasis were unknown. Since 2012 Mn related research has increased with the discovery of Slc30a10 as the mammalian Mn efflux transporter.

The role of Mn in both physiology and metabolic disease is incompletely understood. We used diet-induced models of metabolic dysfunction-associated steatohepatitis (MASH) in mice and found significant downregulation of hepatic Slc30a10 with concurrent increases in liver Mn levels, consistent with transcriptomic data from humans with MASH. By depleting Slc30a10 we created a model of Mn excess and found a significant increase in glucose tolerance by Akt activation in liver that is not dependent on the insulin receptor. These results demonstrate that: (i) increased liver Mn may be a pathological feature contributing to MASH progression and (ii) Mn is a distinct mechanism that activates Akt which may be relevant to human health and disease.