Down-regulated STAT3 messenger ribonucleic acid and STAT3 protein in the hypothalamic arcuate nucleus of the obese leptin-deficient (ob/ob) mouse

Leptin is a weight-reducing hormone produced by adipose tissue, which reduc es food intake via hypothalamic leptin receptors and the JAK-STAT signaling pathway. In vivo studies have shown that leptin activates specifically STA TE in the hypothalamus. We have studied the cellular localization of STATE messenger RNA (mRNA) and STAT3 protein in the mouse mediobasal hypothalamus using, respectively, in situ hybridization and immunohistochemistry. Stron g STATE mRNA and STATE immunoreactivity was demonstrated in neurons located in the ventral part of the mouse arcuate nucleus. Comparison of STAT3 mRNA levels in the arcuate nucleus of lean control mice and obese leptin-defici ent ob/ob mice showed that the levels of STATE mRNA in the arcuate nucleus were significantly lower (31% less in ob/ob mice), compared with control mi ce. Hybridization with a probe specific for STAT3 alpha mRNA showed that th e downregulated STATE expression in the arcuate nucleus of ob/ob mice is re presented by STAT3 alpha. There was a marked difference in numbers and inte nsity of STAT3-immunoreactive cell bodies, with virtually no STAT3-immunore active cell bodies in the mediobasal hypothalamus of ob/ob mice, compared w ith control mice. Direct double-labeling immunofluorescence histochemistry of sections from control mice, combining a goat antiserum raised against a peptide sequence present in all leptin receptor isoforms (Ob-R) or a guinea pig antiserum generated to a peptide sequence specific for Ob-Rb with rabb it STATE antiserum, demonstrated colocalization of STAT3 and Ob-R as well a s colocalization of STATE and Ob-Rb. in many cell bodies of the arcuate nuc leus. The results suggest that circulating leptin acts via leptin receptor- /STAT3-containing neurons in the ventral arcuate nucleus and that congenita l leptin deficiency, as seen in obese ob/ob mice, results in a down-regulat ion of STATE mRNA and protein levels.