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

Hiroyuki Mori, Reiko Hanada, Toshikatsu Hanada, Daisuke Aki, Ryuichi Mashima, Hitomi Nishinakamura, Takehiro Torisu, Kenneth R. Chien, Hideo Yasukawa, Akihiko Yoshimura

Research output: Contribution to journalArticle

447 Citations (Scopus)

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-IoxP 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.

Original languageEnglish
Pages (from-to)739-743
Number of pages5
JournalNature Medicine
Volume10
Issue number7
DOIs
Publication statusPublished - 2004 Jul
Externally publishedYes

Fingerprint

Nutrition
Leptin
Brain
Obesity
Cytokines
Diet
Insulin Resistance
Pro-Opiomelanocortin
Insulin
Phosphorylation
High Fat Diet
Adipocytes
Knockout Mice
Weight Gain
Tyrosine
Weight Loss
Rodentia
Homeostasis
Eating
Body Weight

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

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.; Yasukawa, Hideo; Yoshimura, Akihiko.

In: Nature Medicine, Vol. 10, No. 7, 07.2004, p. 739-743.

Research output: Contribution to journalArticle

Mori, H, Hanada, R, Hanada, T, Aki, D, Mashima, R, Nishinakamura, H, Torisu, T, Chien, KR, Yasukawa, H & Yoshimura, A 2004, 'Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity', Nature Medicine, vol. 10, no. 7, pp. 739-743. https://doi.org/10.1038/nm1071
Mori, Hiroyuki ; Hanada, Reiko ; Hanada, Toshikatsu ; Aki, Daisuke ; Mashima, Ryuichi ; Nishinakamura, Hitomi ; Torisu, Takehiro ; Chien, Kenneth R. ; Yasukawa, Hideo ; Yoshimura, Akihiko. / Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. In: Nature Medicine. 2004 ; Vol. 10, No. 7. pp. 739-743.
@article{43b8491d1e9b474ead339c10011ad4f6,
title = "Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity",
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-IoxP 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.",
author = "Hiroyuki Mori and Reiko Hanada and Toshikatsu Hanada and Daisuke Aki and Ryuichi Mashima and Hitomi Nishinakamura and Takehiro Torisu and Chien, {Kenneth R.} and Hideo Yasukawa and Akihiko Yoshimura",
year = "2004",
month = "7",
doi = "10.1038/nm1071",
language = "English",
volume = "10",
pages = "739--743",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "7",

}

TY - JOUR

T1 - Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity

AU - Mori, Hiroyuki

AU - Hanada, Reiko

AU - Hanada, Toshikatsu

AU - Aki, Daisuke

AU - Mashima, Ryuichi

AU - Nishinakamura, Hitomi

AU - Torisu, Takehiro

AU - Chien, Kenneth R.

AU - Yasukawa, Hideo

AU - Yoshimura, Akihiko

PY - 2004/7

Y1 - 2004/7

N2 - 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-IoxP 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.

AB - 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-IoxP 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.

UR - http://www.scopus.com/inward/record.url?scp=3142723983&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=3142723983&partnerID=8YFLogxK

U2 - 10.1038/nm1071

DO - 10.1038/nm1071

M3 - Article

C2 - 15208705

AN - SCOPUS:3142723983

VL - 10

SP - 739

EP - 743

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 7

ER -