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
N1 - Funding Information:
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.
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.
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U2 - 10.1038/nm1071
DO - 10.1038/nm1071
M3 - Article
C2 - 15208705
AN - SCOPUS:3142723983
SN - 1078-8956
VL - 10
SP - 739
EP - 743
JO - Nature Medicine
JF - Nature Medicine
IS - 7
ER -
