Leptin-Induced Nuclear Translocation of STAT3 Immunoreactivity in Hypothalamic Nuclei Involved in Body Weight Regulation

Abstract

Leptin is involved in the hypothalamic control of food intake and body weight. Fos immunohistochemistry has been used to functionally map leptin target neurons involved in these regulatory processes. However, only a subset of hypothalamic neurons expressing the long form of the leptin receptor (Ob-Rb) also coexpress the neuronal activation marker Fos after leptin stimulation. To functionally map all leptin target neurons, regardless of whether leptin-mediated neuronal activation or inhibition occurs, we immunohistochemically investigated the leptin-induced nuclear translocation of the signal transducer and activator of transcription molecule STAT3, which represents a crucial step in the regulation of leptin-dependent gene expression. As proven by colocalization studies with the nuclear 4Ј,6-diamidino-2-phenylindole dilactate stain, intracerebroventricular leptin treatment, but not intracerebroventricular application of pyrogen-free saline, induced a time-dependent nuclear translocation of STAT3 immunoreactivity in hypothalamic nuclei, with strong nuclear STAT3 signals detectable in the arcuate nucleus, the lateral hypothalamus, and the ventromedial and dorsomedial hypothalamic nuclei. This leptininduced STAT3 translocation pattern proved to be distinct from that induced by interleukin-6, another cytokine using STAT3 in its signaling pathway. Combined immunohistochemical STAT3 and Fos detection after leptin treatment revealed a higher number of STAT3-positive than Fos-positive cell nuclei in the aforementioned hypothalamic structures and showed that Fos immunoreactivity colocalized only in a subset of all leptinresponsive STAT3 nuclei. These results suggest that the detection of nuclear STAT3 immunoreactivity represents a new neuroanatomical tool to functionally map central leptin actions. They further support the importance of ventrally located caudal hypothalamic structures representing the main leptin targets involved in body weight regulation.

Leptin and Inflammation

“…In particular, the binding of leptin to its receptor activates JAK2 which becomes auto-phosphorylated and in turn phosphorylates tyrosine residues on the intracellular domain of the receptor for the binding and activation of signal transducers and activators of transcription (STATS) including STAT1, STAT3, STAT5 and STAT6 (in a variety of cell types). STAT3 activation regulates the expression of different genes that mediate the effects of leptin on cell growth and function as well as on the activation of peripheral mononuclear cells including lymphocytes and macrophages [45][46][47]. In addition, STAT3 regulates the activation of suppressors of cytokine signaling 3 (SOCS3), a member of a family of anti-inflammatory cytokines that suppress cellular responses to inflammatory cytokines which participate in an inhibitory feedback loop of leptin signaling [48].…”

The role of the endocannabinoid system in the control of energy homeostasis

“…26 CB1 receptors are expressed in areas of the hypothalamus involved in appetite control, such as the paraventricular nucleus (PVN), where they are expressed in CRH-and CART-containing neurons, and in the lateral hypothalamus, where they are present in orexin-and melanin concentrating hormone (MCH)-containing neurons. 27 This latter site is of particular interest, as orexinand MCH neurons also express functional leptin receptors, 28,29 and they have dense projections to dopaminergic neurons in the ventral tegmental area, 30 where they modulate the mesolimbic dopaminergic pathway involved in food reward. Thus, they are a likely site for the proposed leptin/ endocannabinoid interaction in the control of food intake, 22 and could also represent a site of integration of hypothalamic and extrahypothalamic structures involved in the orexigenic effect of endocannabinoids.…”

Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice

“…Leptin can bind to the hypothalamic leptin receptor and activates the JAK2 (Janus kinase-2)-STAT3 (signal transducer and activator of transcription-3) pathway that promotes negative energy balance [5]. Besides the JAK2-STAT3 pathway, leptin also acts through the serine/threonine protein kinase B (PKB)/Akt signaling pathway to induce forkhead box protein O1 (FOXO1) phosphorylation and degradation, and decrease FOXO1 activity in the hypothalamus [6].…”