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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Acknowledgements
We thank Y. Kawabata for technical assistance; N. Arifuku, F. Yamaura and Y. Nishi for manuscript preparation; P. Kievit and J.S. Flier for discussions; and M. Ohara for language assistance. Supported by special grants-in-aid from the Ministry of Education, Science, Technology, Sports, and Culture of Japan, the Japan Health Science Foundation, Mochida Memorial Foundation, and the Uehara Memorial Foundation.
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Supplementary information
Supplementary Fig. 1
Expression of Cre and Socs3 in various tissues. (PDF 11854 kb)
Supplementary Fig. 2
Response of body weight to various dose of leptin. (PDF 126 kb)
Supplementary Fig. 3
Serum leptin levels after leptin administration. (PDF 89 kb)
Supplementary Fig. 4
Plasma free-fatty acid and triglyceride levels. (PDF 53 kb)
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Mori, H., Hanada, R., Hanada, T. et al. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat Med 10, 739–743 (2004). https://doi.org/10.1038/nm1071
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DOI: https://doi.org/10.1038/nm1071
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