Specific Physiological Roles for Signal Transducer and Activator of Transcription 3 in Leptin Receptor-Expressing Neurons
Open Access
- 1 March 2008
- journal article
- other
- Published by The Endocrine Society in Molecular Endocrinology
- Vol. 22 (3), 751-759
- https://doi.org/10.1210/me.2007-0389
Abstract
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.Keywords
This publication has 25 references indexed in Scilit:
- Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animalsNature Medicine, 2006
- Central nervous system control of food intake and body weightNature, 2006
- Critical role of STAT3 in leptin's metabolic actionsCell Metabolism, 2006
- Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenesJCI Insight, 2005
- Roles for leptin receptor/STAT3-dependent and -independent signals in the regulation of glucose homeostasisCell Metabolism, 2005
- Essential Role of STAT3 in Body Weight and Glucose HomeostasisMolecular and Cellular Biology, 2004
- STAT3 signalling is required for leptin regulation of energy balance but not reproductionNature, 2003
- Selective deletion of leptin receptor in neurons leads to obesityJCI Insight, 2001
- Selective deletion of leptin receptor in neurons leads to obesityJCI Insight, 2001
- Evidence That the Diabetes Gene Encodes the Leptin Receptor: Identification of a Mutation in the Leptin Receptor Gene in db/db MiceCell, 1996