The Role of SOCS-3 in Leptin Signaling and Leptin Resistance*
- From the ‡Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215 and ¶Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215
Abstract
We earlier demonstrated that leptin induces expression of SOCS-3 mRNA in the hypothalamus. Furthermore, transfection data suggest that SOCS-3 is an inhibitor of leptin signaling. However, little is known about the regulation of SOCS-3 expression by leptin and the mechanism by which SOCS-3 inhibits leptin action. We here show that in CHO cells stably expressing the long form of the leptin receptor (CHO-OBRl), leptin induces transient expression of endogenous SOCS-3 mRNA but not of CIS, SOCS-1, or SOCS-2 mRNA. SOCS-3 protein levels were maximal after 2–3 h of leptin treatment and remained elevated at 20 h. Furthermore, in leptin-pretreated CHO-OBRl cells, proximal leptin signaling was blocked for more than 20 h after pretreatment, thus correlating with increased SOCS-3 expression. Leptin pretreatment did not affect cell surface expression of leptin receptors as measured by125I-leptin binding assays. In transfected COS cells, forced expression of SOCS-3 results in inhibition of leptin-induced tyrosine phosphorylation of JAK2. Finally, JAK2 co-immunoprecipitates with SOCS-3 in lysates from leptin-treated COS cells. These results suggest that SOCS-3 is a leptin-regulated inhibitor of proximal leptin signaling in vivo. Excessive SOCS-3 activity in leptin-responsive cells is therefore a potential mechanism for leptin resistance, a characteristic feature in human obesity.
Footnotes
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↵* This work was supported by National Institutes of Health Grant DK R37 28082 and a grant from Lilly (to J. S. F.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵§ These authors contributed equally to this work.
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↵‖ To whom correspondence should be addressed: Division of Endocrinology, Dept. of Medicine, Beth Israel Deaconess Medical Center, 99 Brookline Ave., Research North, Boston, MA 02215. Tel.: 617-667-2151; Fax: 617-667-2927; E-mail: jflier@caregroup.harvard.edu.
- Abbreviations:
- STAT
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signal transducers and activators of transcription
- EPO
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erythropoietin
- TNF
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tumor necrosis factor
- CHO
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Chinese hamster ovary
- EMSA
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electrophoretic mobility shift assay
- HA
-
hemagglutinin
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- Received March 12, 1999.
- Revision received June 11, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
