Article

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: 14.46). 04/1998; 1(4):619-25. DOI: 10.1016/S1097-2765(00)80062-3
Source: PubMed

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. "
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    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 [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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    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). "
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