Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity.
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.
Mori
Hiroyuki
H
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Hanada
Reiko
R
Hanada
Toshikatsu
T
Aki
Daisuke
D
Mashima
Ryuichi
R
Nishinakamura
Hitomi
H
Torisu
Takehiro
T
Chien
Kenneth R
KR
Yasukawa
Hideo
H
Yoshimura
Akihiko
A
D000818:Animals; D001923:Brain Chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D004435:Eating / Q000187:drug effects; D005260:Female; D007333:Insulin Resistance; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009765:Obesity / Q000517:prevention & control*; D010766:Phosphorylation; D012097:Repressor Proteins / Q000032:analysis / Q000037:antagonists & inhibitors; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000032:analysis / Q000037:antagonists & inhibitors / Q000172:deficiency*; D015431:Weight Loss / Q000187:drug effects
D004268:DNA-Binding Proteins; D004041:Dietary Fats; D020738:Leptin; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors