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 reduces food intake via hypothalamic leptin receptors and the JAK-STAT signaling pathway. In vivo studies have shown that leptin activates specifically STATE 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. Strong 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-deficient 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 mice. Hybridization with a probe specific for STAT3 alpha mRNA showed that the downregulated STATE expression in the arcuate nucleus of ob/ob mice is represented by STAT3 alpha. There was a marked difference in numbers and intensity of STAT3-immunoreactive cell bodies, with virtually no STAT3-immunoreactive cell bodies in the mediobasal hypothalamus of ob/ob mice, compared with 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 rabbit STATE antiserum, demonstrated colocalization of STAT3 and Ob-R as well as colocalization of STATE and Ob-Rb. in many cell bodies of the arcuate nucleus. The results suggest that circulating leptin acts via leptin receptor-/STAT3-containing neurons in the ventral arcuate nucleus and that congenital leptin deficiency, as seen in obese ob/ob mice, results in a down-regulation of STATE mRNA and protein levels.