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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    • "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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    • "ential mechanisms for leptin resistance has been proposed and include defective transport of leptin across the blood - brain barrier ( Bjørbaek and Kahn , 2004 ; Flier , 2004 ) , defects in leptin receptor / post - receptor signalling cascade through molecular mediators of leptin resistance such as suppressor of cytokine signalling - 3 ( SOCS3 ) ( Bjørbaek et al . , 1998 ) and protein tyrosine phosphatase 1B ( PTP1B ) ( Cheng et al . , 2002 ) , and a desensitization of cellular downstream signalling at central and peripheral level ( Münzberg and Myers , 2005 ) . Finally , in this context , leptin desensitization found in obese humans can affect the regulation of lipid and glucose handling in the AT , mu"
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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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