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Cited by 90Adipokines, Inflammation, and Metabolic DiseasesCytokine Signaling Pathways and InteractionsRegulation of Appetite and Obesity

Regulation of Insulin and Leptin Signaling by Muscle Suppressor of Cytokine Signaling 3 (SOCS3)

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Yang, Zhenggang, Hulver, Matthew, McMillan, Ryan P., Cai, Lingzhi, Kershaw, Erin E., Yu, Liqing, Xue, Bingzhong, Shi, Hang·2012·PLoS ONE
DOI 10.1371/journal.pone.0047493PMC PMC3480378
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Abstract

Skeletal muscle resistance to the key metabolic hormones, leptin and insulin, is an early defect in obesity. Suppressor of cytokine signaling 3 (SOCS3) is a major negative regulator of both leptin and insulin signaling, thereby implicating SOCS3 in the pathogenesis of obesity and associated metabolic abnormalities. Here, we demonstrate that SOCS3 mRNA expression is increased in murine skeletal muscle in the setting of diet-induced and genetic obesity, inflammation, and hyperlipidemia. To further evaluate the contribution of muscle SOCS3 to leptin and insulin resistance in obesity, we generated transgenic mice with muscle-specific overexpression of SOCS3 (MCK/SOCS3 mice). Despite similar body weight, MCK/SOCS3 mice develop impaired systemic and muscle-specific glucose homeostasis and insulin action based on glucose and insulin tolerance tests, hyperinsulinemic-euglycemic clamps, and insulin signaling studies. With regards to leptin action, MCK/SOCS3 mice exhibit suppressed basal and leptin-stimulated activity and phosphorylation of alpha2 AMP-activated protein kinase (α2AMPK) and its downstream target, acetyl-CoA carboxylase (ACC). Muscle SOCS3 overexpression also suppresses leptin-regulated genes involved in fatty acid oxidation and mitochondrial function. These studies demonstrate that SOC3 within skeletal muscle is a critical regulator of leptin and insulin action and that increased SOCS may mediate insulin and leptin resistance in obesity.

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  • Transient IL-6/STAT3 helps maintain glucose homeostasis, while chronic IL-6/STAT3 signaling impairs insulin action, leading to insulin resistance and inflammation-associated glucose intolerance, probably through increased basal SOCS3 levels.

    “whereas transient IL-6/STAT3 seems to be helping maintain glucose homeostasis, chronic IL-6/STAT3 signaling impairs insulin action, leading to insulin resistance and inflammation-associated glucose intolerance, probably through an increase in basal SOCS3 levels”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Yang et al., 2012

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Authors
Yang, Z., Hulver, M., McMillan, R. P., Cai, L., Kershaw, E. E., Yu, L., Xue, B., & Shi, H.
Affiliations
  • First Affiliated Hospital Zhejiang University (CN)
  • Virginia Tech (US)
  • University of Pittsburgh (US)
  • University of Maryland, College Park (US)
  • Georgia State University (US)
Corresponding author
  • Xue, Bingzhong
  • Shi, Hang
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-10-24
Volume
7
Issue
10
Pages
e47493
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0047493
PMC
PMC3480378
OpenAlex
W1994913289
Cited by
90
References
7
Citations by year
2026: 6 · 2025: 6 · 2024: 4 · 2023: 5 · 2022: 5 · 2021: 9 · 2020: 2 · 2019: 5 · 2018: 7 · 2017: 5 · 2016: 10 · 2015: 8 · 2014: 8 · 2013: 10
FWCI
6.23
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • VTechWorks (Virginia Tech) (submittedVersion, cc-by)
Funders
  • American Heart Association (R01HL107500, 11GRNT7370080, 10SDG3900046)
  • National Institutes of Health
  • National Institute on Aging (P30AG-21332, P30AG021332)
  • National Heart, Lung, and Blood Institute (R01HL107500)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK084172)
Topics
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Keywords
SOCS3, skeletal muscle, insulin resistance, leptin resistance, obesity, AMPK, acetyl-CoA carboxylase, glucose homeostasis, fatty acid oxidation, mitochondrial function, hyperlipidemia, inflammation
MeSH terms
Suppressor of Cytokine Signaling 3 Protein, Adenylate Kinase, Animals, Homeostasis, Hyperlipidemias, Inflammation, Insulin, Mice, Transgenic, Obesity, RNA, Messenger, Signal Transduction, Muscle, Skeletal, Leptin, Suppressor of Cytokine Signaling Proteins, Mice

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