Identification of SOCS-3 as a Potential Mediator of Central Leptin Resistance

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Molecular Cell (Impact Factor: 14.02). 04/1998; 1(4):619-25. DOI: 10.1016/S1097-2765(00)80062-3
Source: PubMed


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. "
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    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 · 4.41 Impact Factor
    • "NS, non-stimulated; SOCS3, suppressor of cytokine signaling-3; TLR-3L, Toll-like receptor-3 ligand. E. Teran-Cabanillas et al. / Nutrition 29 (2013) 207–212 210 a potential mediator of central leptin resistance [23] [24]. "
    2nd Annual Meeting of the International-Cytokine-and-Interferon-Society; 11/2014
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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 [11]. Therefore, we compared hypothalamic SOCS3 mRNA expression between mice consuming the low-fat regular diet and the HFD (Figure 3B). "
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    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.
    Molecular Metabolism 09/2014; 3(6). DOI:10.1016/j.molmet.2014.06.001
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