Leptin activation of Stat3 in the hypothalamus of wild–type and ob/ob mice but not db/db mice

Abstract

Leptin, a hormone secreted by adipocytes, regulates the size of the adipose tissue mass through effects on satiety and energy metabolism. Leptin's precise sites of action are not known. The leptin receptor (Ob-R) is found in many tissues in several alternatively spliced forms raising the possibility that leptin exerts effects on many tissues including the hypothalamus. Ob-R is a member of the gp130 family of cytokine receptors which are known to stimulate gene transcription via activation of cytosolic STAT proteins. In order to identify the sites of leptin action in vivo, we assayed for activation of STAT proteins in mice treated with leptin. The STAT proteins bind to phosphotyrosine residues in the cytoplasmic domain of the ligand-activated receptor where they are phosphorylated. The activated STAT proteins dimerize and translocate to the nucleus where they bind DNA and activate transcription. The activation of STAT proteins in response to leptin was assayed in a variety of mouse tissues known to express Ob-R. Leptin injection activated Stat3 but no other STAT protein in the hypothalamus of ob/ob and wild-type mice but not db/db mice, mutants that lack an isoform of the leptin receptor. Leptin did not induce STAT activation in any of the other tissues tested. Activation of Stat3 by leptin was dose dependent and first observed after 15 minutes and maximal at 30 minutes. Our data indicate the hypothalamus is a direct target of leptin action and that this activation is critically dependent on the gp-130-like leptin receptor isoform missing in C57BLKS/J db/db mice. This is the first in vivo demonstration of leptin signal transduction.

Regulation of corticotropin-releasing factor and urocortin 2/3 mRNA by leptin in hypothalamic N39 cells

“…Leptin activates STAT3 with Jak2. Leptin similarly stimulates STAT3 phosphorylation in the rodent hypothalamus [60] and hypothalamic N39 cells. A JAK inhibitor inhibits the leptin-mediated increase in STAT3 phosphorylation.…”

“…Through the activation Ob-Rb and subsequent activation of the Jak2-STAT3 signaling pathway in the hypothalamus, leptin reduces food intake and boosts energy expenditure [53,60].…”

“…Ob-Rb is well-known to mediate the effects of leptin through the Janus kinase (JAK)-signal transducer and activators of transcription (STAT) pathway [22], although in the rodent hypothalamus, leptin activates only STAT type 3 (STAT3) [60].…”

Lack of starvation-induced activation of AMP-activated protein kinase in the hypothalamus of the Lou/C rats resistant to obesity

“…This could be due to upregulation of ObRb gene expression in this condition (Table 3), confirming previous reports showing that the leptin-mediated phosphorylation of STAT3 is specifically dependent on this isoform of leptin receptor. 34,35 More importantly, while circulating leptin and STAT3 phosphorylation were clearly decreased by starvation in Wistar rats, they remained unaffected in starved Lou/C rats, so that STAT3 phosphorylation was almost 50% higher in Lou/C Figure 4 Proposed mechanism for the lack of starvation-induced hypothalamic AMPK activation and hypophagia in Lou/C rats. Starvation fails to activate AMPK in the hypothalamus of the Lou/C rats (right panel) in contrast with Wistar rats (left panel).…”

Body weight is regulated by the brain: a link between feeding and emotion

“…50,51 The Ob-R has a single transmembrane spanning domain and functions via the JAK-STAT pathway. 51,52 Thus far, splice variants of Ob-R mRNA encoding six isoforms have been identified, and only the long form (Ob-Rb) has intracellular signaling motifs of leptin. 51 Consequently, the db/db mice lacking Ob-Rbs and ob/ob mice exhibit an almost identical obesity phenotype.…”