Cited by 651Regulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic DiseasesCytokine Signaling Pathways and Interactions

Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity

Mori, Hiroyuki, Hanada, Reiko, Hanada, Toshikatsu, Aki, Daisuke, Mashima, Ryuichi, Nishinakamura, Hitomi, Torisu, Takehiro, Chien, Kenneth R +2 more·2004·Nature Medicine

Abstract

Leptin is an adipocyte-derived hormone that plays a key role in energy homeostasis, yet resistance to leptin is a feature of most cases of obesity in humans and rodents. In vitro analysis suggested that the suppressor of cytokine signaling-3 (Socs3) is a negative-feedback regulator of leptin signaling involved in leptin resistance. To determine the functional significance of Socs3 in vivo, we generated neural cell-specific SOCS3 conditional knockout mice using the Cre-loxP system. Compared to their wild-type littermates, Socs3-deficient mice showed enhanced leptin-induced hypothalamic Stat3 tyrosine phosphorylation as well as pro-opiomelanocortin (POMC) induction, and this resulted in a greater body weight loss and suppression of food intake. Moreover, the Socs3-deficient mice were resistant to high fat diet-induced weight gain and hyperleptinemia, and insulin-sensitivity was retained. These data indicate that Socs3 is a key regulator of diet-induced leptin as well as insulin resistance. Our study demonstrates the negative regulatory role of Socs3 in leptin signaling in vivo, and thus suppression of Socs3 in the brain is a potential therapy for leptin-resistance in obesity.

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Crossref · 10.1038/nm1071

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Authors
Mori, H., Hanada, R., Hanada, T., Aki, D., Mashima, R., Nishinakamura, H., Torisu, T., Chien, K. R., Yasukawa, H., & Yoshimura, A.
Affiliations
  • Kyushu University (JP)
  • Kurume University (JP)
  • University of California San Diego (US)
Corresponding author
Yoshimura, Akihiko
Venue
Nature Medicine
Published
2004-06-20
Volume
10
Issue
7
Pages
739-743
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
OpenAlex
W2042621509
Cited by
651
References
29
Citations by year
2026: 9 · 2025: 17 · 2024: 19 · 2023: 15 · 2022: 20 · 2021: 20 · 2020: 11 · 2019: 25 · 2018: 21 · 2017: 21 · 2016: 36 · 2015: 38 · 2014: 41 · 2013: 38 · 2012: 46
FWCI
15.28
Type
journal article
Language
en
Open access
closed
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
Funders
Japan Health Sciences Foundation
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
SOCS3, leptin resistance, leptin signaling, diet-induced obesity, hypothalamus, STAT3 tyrosine phosphorylation, proopiomelanocortin, hyperleptinemia, insulin resistance, energy homeostasis, dietary intake, weight loss
MeSH terms
Suppressor of Cytokine Signaling 3 Protein, Animals, Brain Chemistry, Dietary Fats, DNA-Binding Proteins, Eating, Female, Insulin Resistance, Male, Obesity, Phosphorylation, Repressor Proteins, Transcription Factors, Weight Loss, Trans-Activators, Leptin, STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins, Mice

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