PDX1 phosphorylation at S61 by mTORC1 links nutrient signaling to β cell function and metabolic disease

PDX1 is a key transcription factor regulating insulin expression in response to glucose. Our previous work showed that PDX1 is also stimulated by amino acids (aa). Here, we demonstrate that PDX1 broadly mediates aa-regulated transcriptional programs in β cells, especially those controlling β cell proliferation and function. Mechanistically, mTORC1 phosphorylates PDX1 at serine 61 (S61), enhancing its protein stability and transcriptional activity. A certain monogenic diabetes mutation disrupts this phosphorylation and impairs PDX1 function. To investigate its physiological role, we generated mice carrying S61A and S61E mutations, mimicking unphosphorylated and phosphorylated states. S61 phosphorylation promoted insulin expression and β cell proliferation, leading to Western diet-induced hyperinsulinemia, obesity, and hepatic steatosis. These findings reveal the central role of aa-mTORC1-PDX1 signaling in coordinating β cell proliferation and function under both physiological and pathological conditions.