Leptin-induced nuclear translocation of STAT3 immunoreactivity in hypothalamic nuclei involved in body weight regulation

Leptin is involved in the hypothalamic control of food intake and body weig ht. Fos immunohistochemistry has been used to functionally map leptin targe t neurons involved in these regulatory processes. However, only a subset of hypothalamic neurons expressing the long form of the leptin receptor (Ob-R b) also coexpress the neuronal activation marker Fos after leptin stimulati on. To functionally map all leptin target neurons, regardless of whether le ptin-mediated neuronal activation or inhibition occurs, we immunohistochemi cally investigated the leptin-induced nuclear translocation of the signal t ransducer and activator of transcription molecule STAT3, which represents a crucial step in the regulation of leptin-dependent gene expression. As pro ven by colocalization studies with the nuclear 4',6-diamidino-2-phenylindol e dilactate stain, intracerebroventricular leptin treatment, but not intrac erebroventricular application of pyrogen-free saline, induced a time-depend ent nuclear translocation of STAT3 immunoreactivity in hypothalamic nuclei, with strong nuclear STAT3 signals detectable in the arcuate nucleus, the l ateral hypothalamus, and the ventro-medial and dorsomedial hypothalamic nuc lei. This leptin-induced STAT3 translocation pattern proved to be distinct from that induced by interleukin-6, another cytokine using STAT3 in its sig naling pathway. Combined immunohistochemical STAT3 and Fos detection after leptin treatment revealed a higher number of STAT3-positive than Fos-positi ve cell nuclei in the aforementioned hypothalamic structures and showed tha t Fos immunoreactivity colocalized only in a subset of all leptin-responsiv e STAT3 nuclei. These results suggest that the detection of nuclear STAT3 i mmunoreactivity represents a new neuroanatomical tool to functionally map c entral leptin actions. They further support the importance of ventrally loc ated caudal hypothalamic structures representing the main leptin targets in volved in body weight regulation.