Identification of SOCS-3 as a Potential Mediator of Central Leptin Resistance
ABSTRACT Leptin affects food intake and body weight by actions on the hypothalamus. Although leptin resistance is common in obesity, mechanisms have not been identified. We examined the effect of leptin on expression of the suppressors-of-cytokine-signaling (SOCS) family of proteins. Peripheral leptin administration to ob/ob, but not db/db mice, rapidly induced SOCS-3 mRNA in hypothalamus, but had no effect on CIS, SOCS-1, or SOCS-2. A leptin-dependent increase of SOCS-3 mRNA was seen in areas of hypothalamus expressing high levels of the leptin receptor long form. In mammalian cell lines, SOCS-3, but not CIS or SOCS-2, blocked leptin-induced signal transduction. Expression of SOCS-3 mRNA in the arcuate and dorsomedial hypothalamic nuclei is increased in Ay/a mice, a model of leptin-resistant murine obesity. In conclusion, SOCS-3 is a leptin-inducible inhibitor of leptin signaling, and a potential mediator of leptin resistance in obesity.
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- "The use of leptin as a therapeutic agent has been explored with limited success due to this inability to respond to circulating levels of leptin. Possible reasons for this include a defect in the transport of leptin across the blood–brain barrier (Banks, 2004), inhibition of the intracellular signaling from the leptin receptor mediated by increased expression of Suppressor of Cytokine signaling 3 (SOCS3) (Bjorbaek et al., 1998; Howard et al., 2004; Liu et al., 2011; Mori et al., 2004) or other effects on cellular signaling pathways. "
ABSTRACT: In a world with increasing incidences of obesity, it becomes critical to understand the detailed regulation of appetite. To identify novel regulators of the signaling mediated by one of the key hormones of energy homeostasis, leptin, we screened a set of compounds for their effect on the downstream Signal Transducer and Activator of Transcription 3 (STAT3) signaling. Interestingly, cells exposed to inhibitors of the Ataxia Telangiectasia and RAD3- related protein ATR increased their leptin dependent STAT3 activity. This was due to failure of the cells to induce the negative feedback mediator Suppressor of Cytokine Signaling 3 (SOCS3), suggesting that ATR has a previously unknown role in the negative feedback regulation of leptin signaling. This is an important finding not only because it sheds light on additional genes involved in leptin signaling, but also because it brings forward a new potential therapeutic intervention point for increasing leptin signaling in obese individuals. Copyright © 2015. Published by Elsevier Ireland Ltd.Molecular and Cellular Endocrinology 05/2015; 275. DOI:10.1016/j.mce.2015.04.034 · 4.24 Impact Factor
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- "However, leptin infusion failed to increase the hypothalamic SOCS3 expression in LepR SOCS3 KO mice (Figure 3A). Obese animals have been shown to have higher hypothalamic SOCS3 expression . Therefore, we compared hypothalamic SOCS3 mRNA expression between mice consuming the low-fat regular diet and the HFD (Figure 3B). "
ABSTRACT: Therapies that improve leptin sensitivity have potential as an alternative treatment approach against obesity and related comorbidities. We investigated the effects of Socs3 gene ablation in different mouse models to understand the role of SOCS3 in the regulation of leptin sensitivity, diet-induced obesity (DIO) and glucose homeostasis. Neuronal deletion of SOCS3 partially prevented DIO and improved glucose homeostasis. Inactivation of SOCS3 only in LepR-expressing cells protected against leptin resistance induced by HFD, but did not prevent DIO. However, inactivation of SOCS3 in LepR-expressing cells protected mice from diet-induced insulin resistance by increasing hypothalamic expression of Katp channel subunits and c-Fos expression in POMC neurons. In summary, the regulation of leptin signaling by SOCS3 orchestrates diet-induced changes on glycemic control. These findings help to understand the molecular mechanisms linking obesity and type 2 diabetes, and highlight the potential of SOCS3 inhibitors as a promising therapeutic approach for the treatment of diabetes.09/2014; 3(6). DOI:10.1016/j.molmet.2014.06.001
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- "SOCS-1 interferes with STAT-1 phosphorylation and thereby attenuates signalling of interferon-␥ (IFN-␥), IL-2, IL-4, IL-6, IL-12, IL-15 and tumor necrosis factor-␣ (TNF-␣) (Davey et al., 2006; Murray, 2007). SOCS-3 is induced by IL-6-type cytokines and is essential for the suppression of IL-6/glycoprotein 130 (gp130) signalling (Sommer et al., 2005), and can interact with the receptors for leptin, EPO and granulocyte colony-stimulating factor (G-CSF) (Bjorbaek et al., 1998; Marine et al., 1999). Both SOCS-1 and -3 can inhibit IFN-␣-induced expression of antiviral proteins (Vlotides et al., 2004) and SOCS gene expression induced by chemokines and some toll-like receptor (TLR) agonists (Dalpke et al., 2001; Hu et al., 2009). "
ABSTRACT: Suppressor of cytokine signalling (SOCS) family members are crucial in the control and attenuation of cytokine induced responses via activation of the JAK/STAT, TLR and NF-kB signalling pathways. SOCS proteins orchestrate the termination of many types of immune responses and are often the targets of microbial pathogens exploiting SOCS mechanisms to evade the host's immune response. Through whole and lineage specific genome duplication events, the teleost cytokine/SOCS network is complex. Not only are the orthologues of all mammalian SOCS members present, namely cytokine inducible Src homology 2 (SH2)-containing protein (CISH) and SOCS-1 to -7, but multiple gene copies exist that may potentially become functionally divergent. In this paper we focus on the CISH genes in rainbow trout (Oncorhynchus mykiss), and have cloned two further paralogues, CISHa2 and CISHb2, additional to the known CISHa1 and CISHb1 genes. We present for the first time a comparative expression analysis of these four paralogues, to establish whether subfunctionalisation is apparent. In vivo examination of gene expression revealed a higher constitutive expression level of CISHa paralogues compared to CISHb expression in adult trout tissues. All CISHs were relatively highly abundant in immune tissues but CISHa2 and CISHb2 had highest expression in the heart and muscle. An inverse picture of CISH abundance during trout ontogeny was seen, and further hints at differential roles of the four genes in immune regulation and development. Stimulation of head kidney (HK) leukocytes with trout recombinant interleukin (rIL)-15 and rIL-21 had a major effect on CISHa2 and to a lesser extent CISHa1 expression. In HK macrophages rIL-1β, phytohemagglutinin, and phorbol 12-myristate 13-acetate also had a strong impact on CISHa2 expression. Yersinia ruckeri infection caused a temporally and spatially differential onset of CISH expression that may be viewed in the context of pathogen evasion strategies. These data, against the backdrop of fish specific whole genome duplication events and functional divergence, provide the first evidence for differential roles of the four trout CISH genes in immune control and development.Molecular Immunology 07/2014; 62(1):186-198. DOI:10.1016/j.molimm.2014.06.021 · 3.00 Impact Factor