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Inhibition of Preproinsulin Gene Expression by Leptin Induction of Suppressor of Cytokine Signaling 3 in Pancreatic ß-Cells

¹ Division of Metabolism, Endocrinology and Molecular Medicine, Medizinische Klinik and Poliklinik II, University of Würzburg, Würzburg, Germany
² Laboratory of Molecular and Cellular Medicine, the Departments of Cellular and Physiological Sciences and Surgery, University of British Columbia, Vancouver, British Columbia, Canada

Leptin inhibits insulin secretion and preproinsulin gene expression in pancreatic ß-cells, but signal transduction pathways and molecular mechanisms underlying this effect are poorly characterized. In this study, we analyzed leptin-mediated signal transduction and preproinsulin gene regulation at the molecular level in pancreatic ß-cells. Leptin stimulation led to janus kinase (JAK)2-dependent phosphorylation and nuclear translocation of the transcription factors signal transducer and activator of transcription (STAT)3 and STAT5b in INS-1 ß-cells. Leptin also induced mRNA expression of the JAK-STAT inhibitor suppressor of cytokine signaling (SOCS)3 in INS-1 ß-cells and human pancreatic islets in vitro and in pancreatic islets of ob/ob mice in vivo. Transcriptional activation of the rat SOCS3 promoter by leptin was observed with concomitant leptin-induced STAT3 and STAT5b DNA binding to specific promoter regions. Unexpectedly, SOCS3 inhibited both basal and STAT3/5b-dependent rat preproinsulin 1 gene promoter activity in INS-1 cells. These results suggest that SOCS3 represents a transcriptional inhibitor of preproinsulin gene expression, which is induced by leptin through JAK-STAT3/5b signaling in pancreatic ß-cells. In conclusion, although SOCS3 is believed to be a negative feedback regulator of JAK-STAT signaling, our findings suggest involvement of SOCS3 in a direct gene regulatory pathway downstream of leptin-activated JAK-STAT signaling in pancreatic ß-cells.

Abbreviations: GFP, green fluorescent protein; JAK, janus kinase; PY, anti-phosphotyrosine; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription; STATRE, STAT-responsive element

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