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: 14.02). 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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    • "to the SOCS protein family, which is rapidly induced by cytokines, and acts as an inhibitor of various cytokine signaling pathways. Previous studies have shown that SOCS3 is linked to phenotype by being a negative regulator of leptin[9,10]and insulin signaling[17,42,45]. In addition, there is evidence for association between variants located near SOCS3 with glucose homeostasis, BMI, and other obesity traits[50,51]. "
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    • "However, the mechanisms mediating leptin resistance are incompletely understood. To date, studies suggest that high blood leptin concentrations result in saturation of leptin transport across the blood brain barrier (blood brain barrier resistance) (Banks & Lebel 2002) and/or down regulation of leptin signaling in the hypothalamus due to constitutive expression of suppressor of cytokine signaling (hypothalamic resistance ) (Bjorbaek et al. 1998). "
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    • "The adipocyte-derived hormone leptin is a pleiotropic hormone that affects multiple physiological processes, including appetite, body weight, neuroendocrine function, and emotional behaviors (Bjorbaek et al., 1998;Friedman and Halaas, 1998;Schwartz et al., 2000;Lu et al., 2006;Lu, 2007;Liu et al., 2010Liu et al., , 2011Guo et al., 2012Guo et al., , 2013Guo and Lu, 2014;Wang et al., 2015). Previous studies have shown that systemic administration of leptin elicits anxiolytic-like effects in mice (Liu et al., 2010) and rats (Haque et al., 2013). "

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