The role of SOCS-3 in leptin signaling and leptin resistance

Bjørbæk, Christian; El-Haschimi, Karim; Frantz, J. Daniel; Flier, Jeffrey S.

doi:10.1074/jbc.274.42.30059

Cited by 639Regulation of Appetite and ObesityCytokine Signaling Pathways and InteractionsAdipokines, Inflammation, and Metabolic Diseases

The role of SOCS-3 in leptin signaling and leptin resistance

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Bjørbæk, Christian, El-Haschimi, Karim, Frantz, J. Daniel, Flier, Jeffrey S.·1999·Journal of Biological Chemistry

DOI 10.1074/jbc.274.42.30059

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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 by (125)I-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.

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SOCS-3 protein interferes with leptin signaling, causing leptin resistance.
“SOCS-3 protein also interferes with leptin signaling, thus causing leptin resistance [6].”
From Bariatric surgery: remission of inflammation, cardiometabolic benefits, and common adverse effects (2020) · cites this paper as [6]

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Elmquist (1998) · doi:10.1002/(sici)1096-9861(19980615)395:4

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Authors: Bjørbæk, C., El-Haschimi, K., Frantz, J. D., & Flier, J. S.
Affiliations: Beth Israel Deaconess Medical Center (US)
Joslin Diabetes Center (US)
Corresponding author: Flier, Jeffrey S.
ORCID: Flier, Jeffrey S.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 1999-10
Volume: 274
Issue: 42
Pages: 30059-30065
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.274.42.30059
OpenAlex: W2091484442
Cited by: 639
References: 52
Citations by year: 2026: 1 · 2025: 9 · 2024: 9 · 2023: 8 · 2022: 11 · 2021: 14 · 2020: 18 · 2019: 20 · 2018: 17 · 2017: 19 · 2016: 19 · 2015: 20 · 2014: 34 · 2013: 33 · 2012: 31
FWCI: 9.91
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 7680 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: National Institute of Diabetes and Digestive and Kidney Diseases (DK-R37-28082, R37DK028082)
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords: SOCS3, leptin signaling, leptin resistance, leptin receptor, SOCS1, SOCS2, obesity, hypothalamus, signal transduction inhibition
MeSH terms: Suppressor of Cytokine Signaling 3 Protein, Animals, Carrier Proteins, Gene Expression Regulation, Cricetinae, Humans, Proteins, Receptors, Cell Surface, Recombinant Proteins, Repressor Proteins, RNA, Messenger, Transcription Factors, Signal Transduction, CHO Cells, Leptin, Suppressor of Cytokine Signaling Proteins, Receptors, Leptin

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The role of SOCS-3 in leptin signaling and leptin resistance

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