Specific physiological roles for signal transducer and activator of transcription 3 in leptin receptor-expressing neurons

Mol Endocrinol. 2008 Mar;22(3):751-9. doi: 10.1210/me.2007-0389. Epub 2007 Dec 20.


Leptin is a fat-derived hormone that exerts pleiotropic effects on energy balance and neuroendocrine functions. Mice defective in leptin or its receptor [leptin receptor, isoform b (LepRb)] exhibit profound obesity, infertility, and reduced linear growth. Leptin binding to its receptor triggers multiple signaling pathways, including signal transducer and activator of transcription 3 (Stat 3), phosphatidylinositol-3-kinase, and ERK. A considerable amount of effort has been focused on how these signaling pathways mediate diverse leptin functions. Mice containing a mutant LepRb incapable of Stat3 signaling are obese but remain fertile with enhanced linear growth. In contrast, deletion of Stat3 in the whole brain with Nestin-Cre results in infertility and decreased linear growth, in addition to obesity. The additional phenotypes of the Nestin-mediated deletion could reflect Stat3 action in non-LepRb neurons or leptin-independent Stat3 actions in LepRb neurons. To resolve this discrepancy and to gain more insight into the metabolic actions of Stat3, we have generated mice in which Stat3 is disrupted specifically in LepRb neurons after the onset of leptin receptor expression. We show that mutant mice exhibit profound obesity with increased linear growth and normal fertility. In addition, impaired glycemic control in these animals correlates with their degree of obesity. These results demonstrate that Stat3 in LepRb neurons does not regulate linear growth or fertility. These results further suggest that leptin's effects on growth and reproduction are mediated by other signaling pathways, and that Stat3-mediated control of these functions is mediated independently of leptin and LepRb neurons.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agouti-Related Protein / biosynthesis
  • Agouti-Related Protein / genetics
  • Animals
  • Blood Glucose / metabolism
  • Body Weight / physiology
  • Eating / physiology
  • Female
  • Hypothalamus / cytology
  • Hypothalamus / physiology*
  • Leptin / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Fluorescence
  • Neurons / metabolism
  • Neurons / physiology*
  • Neuropeptide Y / biosynthesis
  • Neuropeptide Y / genetics
  • Phosphorylation
  • Pro-Opiomelanocortin / biosynthesis
  • Pro-Opiomelanocortin / genetics
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Receptors, Leptin / biosynthesis
  • Receptors, Leptin / genetics
  • Receptors, Leptin / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT3 Transcription Factor / physiology*


  • Agouti-Related Protein
  • Agrp protein, mouse
  • Blood Glucose
  • Leptin
  • Neuropeptide Y
  • RNA, Messenger
  • Receptors, Leptin
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Pro-Opiomelanocortin