Leptin inhibits insulin gene transcription and reverses hyperinsulinemia in leptin-deficient ob/ob mice

Leptin controls feeding behavior and insulin secretion from pancreatic beta -cells, Insulin stimulates the production of leptin, thereby establishing a n adipoinsular axis. Earlier we identified leptin receptors on pancreatic b eta-cells and showed leptin-mediated inhibition of insulin secretion by act ivation of ATP-sensitive potassium channels. Here we examine transcriptiona l effects of leptin on the promoter of the rat insulin I gene in rodent bet a-cells. A fall in levels of preproinsulin mRNA is detected in vivo in isle ts of ob/ob mice 24 h after a single injection of leptin, in isolated ob/ob islets treated with leptin in vitro and in the beta-cell line INS-1 on lep tin exposure when preproinsulin mRNA expression is stimulated by 25 mM gluc ose or 10 nM glucagon-like peptide 1, Under these conditions, transcription al activity of -410 bp of the rat insulin I promoter is inhibited by leptin , whereas transactivation of a 5'-deleted promoter (-307 bp) is not. The -3 07 sequence contains the known glucose-responsive control elements (E2:A3/4 ). Constitutive activation of ATP-sensitive potassium channels by diazoxide does not alter leptin inhibition of preproinsulin mRNA levels. Distinct pr otein-DNA complexes appear on the rat insulin I promoter sequences located between -307 and -410 with nuclear extracts from ob/ob islets in response t o leptin, including a signal transducer and activator of transcription (STA T)5b binding site. These results indicate that leptin inhibits transcriptio n of the preproinsulin gene by altering transcription factor binding to seq uences upstream from the elements (307 bp) that confer glucose responsivity to the rat insulin I gene promoter. Thus leptin exerts inhibitory effects on both insulin secretion and insulin gene expression in pancreatic beta-ce lls, but by different cellular mechanisms.