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

Nat Med. 2004 Jul;10(7):739-43. doi: 10.1038/nm1071. Epub 2004 Jun 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Chemistry*
  • DNA-Binding Proteins / metabolism
  • Dietary Fats / administration & dosage
  • Eating / drug effects
  • Female
  • Insulin Resistance
  • Leptin / pharmacology*
  • Male
  • Mice
  • Obesity / prevention & control*
  • Phosphorylation
  • Repressor Proteins / analysis
  • Repressor Proteins / antagonists & inhibitors
  • STAT3 Transcription Factor
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators / metabolism
  • Transcription Factors / analysis
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / deficiency*
  • Weight Loss / drug effects


  • DNA-Binding Proteins
  • Dietary Fats
  • Leptin
  • Repressor Proteins
  • STAT3 Transcription Factor
  • Socs3 protein, mouse
  • Stat3 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators
  • Transcription Factors