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

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461 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 1
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Mori, H., Hanada, R., Hanada, T., Aki, D., Mashima, R., Nishinakamura, H., Torisu, T., Chien, K. R., Yasukawa, H., & Yoshimura, A. (2004). Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nature medicine, 10(7), 739-743. https://doi.org/10.1038/nm1071