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

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

Merisa L Piper  1 , Elizabeth K Unger, Martin G Myers Jr, Allison W Xu
Affiliations

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

Merisa L Piper et al. Mol Endocrinol. 2008 Mar.

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.

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Figures

Figure 1
Figure 1
Leptin Administration Fails to Induce pStat3 in the Hypothalamus of LepRb-Stat3 Mutant Mice Panels show coronal sections of control and LepRb-Stat3 mutant mice 30 min after ip injection of saline or leptin (5 mg/kg), as indicated (control saline, n = 3; control leptin, n = 5; mutant leptin, n = 3).
Figure 2
Figure 2
Body Weight and Food Intake Are Significantly Increased in LepRb-Stat3 Mutant Mice A, Body weight for males (n for each time point: controls 7, 14, 8, 11, 7, 6, 4; mutants 7, 13, 5, 8, 4, 8, 5). Last two time points represent ages ± 4 wk. B, Body weight for females (n for each time point: controls, 15, 13, 9, 13, 9, 11, 7, 7, 8, 5; mutants 10, 8, 6, 7, 10, 5, 5, 8, 9, 7). Last two time points represent ages ± 4 wk. C, Representative control (left) and mutant (right) littermates, age 8 months. D, Average daily food intake for male mice at 6 wk and 8 months of age (controls n = 4–5; mutants n = 5). *, P < 0.05; **, P < 0.01 between controls and mutants as determined by Student’s t test. Error bars represent sem.
Figure 3
Figure 3
Correlation between Body Weight and Fasted Glucose Levels in Control and LepRb-Stat3 Mutant Mice Mice were fasted for 6 h, and blood glucose was measured in males (A), and females (B) age 20–24 wk. Serum insulin level was measured 4 wk later under the same conditions. Each data point represents a single mouse with its corresponding insulin level. Both males and females show significant correlation between body weight and glucose levels as determined by linear regression analysis using Statistical Package for the Social Sciences (SPSS, Inc., Chicago, IL) (male: r = 0.717, P = 0.01; female: r = 0.645, P = 0.02). #, Low insulin levels of the indicated animal most likely reflects pancreatic β-cell failure.
Figure 4
Figure 4
LepRb-Stat3 Mutant Mice Exhibit Increased Linear Growth A, Length of males as measured by snout to anus distance at 5 and 10 wk of age (5 wk: controls, n = 8; mutants, n = 10; 10 wk: controls, n = 8; mutants, n = 10). B, Length of females at 5 and 10 wk of age (5 wk: controls, n = 3; mutants, n = 3; 10 wk: controls, n = 10; mutants, n = 4). **, P < 0.01 between controls and mutants as determined by Student’s t test. Error bars represent sem.
Figure 5
Figure 5
Neuropeptide Expression in Control and LepRb-Stat3 Mutant Mice Hypothalamic total RNA was extracted from control and LepRb-Stat3 mutant mice that were fed ad libitum. Pomc (A), Npy (B), Agrp (C), and LepRb (D) expression was analyzed by semiquantitative real-time PCR. β-Actin was used as an internal control to normalize expression levels. Control values were set to 1 in the y-axis for easy comparison. (5 wk: controls, n = 7; mutants, n = 8; 10 wk: controls, n = 6; mutants, n = 6). LepRb expression was measured at 10 wk of age. E, Expression of ACTH and NPY immunoreactivity in 6-month-old controls and mutants by immunofluorescence (controls, n = 3; mutants, n = 3). *, P < 0.05; **, P < 0.01 between controls and mutants as determined by Student’s t test. Error bars represent sem.
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