BACKGROUND AND PURPOSELeptin, an important regulator of the energy balance, acts on the brain to inhibit feeding. However, the mechanisms involved in leptin signalling have not yet been fully elucidated. Heat shock protein 90 (HSP90) is a molecular chaperone that is involved in regulating cellular homeostasis. In the present study, we investigated the possible involvement of HSP90 in leptin signal transduction. EXPERIMENTAL APPROACHHEK293 and SH-SY5Y cell lines stably transfected with the Ob-Rb leptin receptor (HEK293 Ob-Rb, SH-SY5Y Ob-Rb) were used in the present study. Phosphorylation of JAK2 and STAT3 was analysed by western blotting. An HSP90 inhibitor was administered i.c.v. into rats and their food intake was analysed. KEY RESULTSThe knock-down of HSP90 in the HEK293 Ob-Rb cell line attenuated leptin-induced JAK2 and STAT3 signalling. Moreover, leptininduced JAK2/STAT3 phosphorylation was markedly attenuated by the HSP90 inhibitors geldanamycin, radicicol and novobiocin. However, these effects were not mediated through previously known factors, which are known to be involved in the development of leptin resistance, such as suppressor of cytokine signalling 3 or endoplasmic reticulum stress. The infusion of an HSP90 inhibitor into the CNS blunted the anorexigenic actions of leptin in rats (male Wister rat). CONCLUSIONS AND IMPLICATIONSHSP90 may be a novel factor involved in leptin-mediated signalling that is linked to anorexia. AbbreviationsER stress, endoplasmic reticulum stress; HSP90, heat shock protein 90; POMC, proopiomelanocortin; PTP1B, protein tyrosine phosphatase-1B; SOCS3, suppressor of cytokine signalling 3
Obesity is a worldwide health problem that urgently needs to be solved. Leptin is an anti-obesity hormone that activates satiety signals to the brain. Evidence to suggest that leptin resistance is involved in the development of obesity is increasing; however, the molecular mechanisms involved remain unclear. We herein demonstrated that 15-deoxy-D 12,14 -prostaglandin J 2 (15d-PGJ 2 ) was involved in the development of leptin resistance. A treatment with 15d-PGJ 2 inhibited the leptin-induced activation of signal transducer and activator of transcription 3 (STAT3) in neuronal cells (SH-SY5Y-Ob-Rb cells). Furthermore, the intracerebroventricular administration of 15d-PGJ 2 reversed the inhibitory effects of leptin on food intake in rats. The peroxisome proliferatoractivated receptor gamma (PPAR-c) antagonist, GW9662, slightly reversed the inhibitory effects of 15d-PGJ 2 on the leptin-induced activation of STAT3 in neuronal cells. The PPAR-c agonist, rosiglitazone, also inhibited leptin-induced STAT3 phosphorylation. Therefore, the inhibitory effects of 15d-PGJ 2 may be mediated through PPAR-c. On the other hand, 15d-PGJ 2 -induced leptin resistance may not be mediated by endoplasmic reticulum stress or suppressor of cytokine signaling 3. The results of the present study suggest that 15d-PGJ 2 is a novel factor for the development of leptin resistance in obesity. Keywords: 15d-PGJ 2 , leptin, PPAR-c, STAT3. Leptin is anti-obesity hormone that was first identified in 1994 by Friedman's group (Zhang et al. 1994). Leptin is mainly secreted from adipose tissue and acts on brain hypothalamic neurons to reduce food intake (Campfield et al. 1995). Several splicing variants of the leptin receptor isoform have been identified to date. Of those, the Ob-Rb leptin receptor is the longest isoform of the leptin receptor and is considered to play an important role in regulating food intake and energy expenditure. The Ob-Rb leptin receptor is mainly expressed on the hypothalamus (Mercer et al. 1996). Leptin was previously shown to activate the Ob-Rb leptin receptor, which in turn induced JAK2-STAT3 signal transduction (Bjørbaek et al. 1997;Hosoi et al. 2002). The essential role of the Ob-Rb receptor-mediated activation of signal transducer and activator of transcription 3 (STAT3) in the anti-obesity effects of leptin have already been demonstrated (Bates et al. 2003). Thus, leptin treatments were initially expected to be useful for treating obesity. However, since most obese patients were in a state of leptin resistance, they did not adequately respond to the actions of leptin.These findings suggested that leptin resistance was involved in the development of obesity (Friedman 2003). The fact that a deeper understanding of the mechanisms underlying leptin resistance is needed represents an active area of research (Hill et al. 2003). Several studies have proposed mechanisms for the development of leptin resistance. Suppressor of cytokine signaling 3 (SOCS3) (Bjørbaek et al. 1998), protein tyrosine phosphatase 1B (Cheng et al...
Leptin is an anti-obesity hormone, which circulates in the blood and acts on neuronal cells in the brain. Leptin activates the leptin receptor Ob-Rb and induces JAK2-STAT3 pathway, thus inducing an anti-obesity action. It has been suggested that most forms of obesity are accompanied by resistance to leptin, that is, insensitivity to the action of the hormone. Obesity is also accompanied by a low-grade inflammation, associated with leptin resistance. In the present study, we investigated the effect of adenosine, which is produced during inflammation, on leptin signaling. We found that adenosine can be transported into the cell and inhibit leptin-induced STAT3 phosphorylation in a neuronal cell line. On the other hand, the leptin-mediated conformational change of Ob-R, analyzed by bioluminescence resonance energy transfer (BRET), was not affected by adenosine. These results suggest that adenosine may inhibit leptin signaling by regulating signaling steps downstream of leptin receptor.
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